bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–05–25
53 papers selected by
Viktor Korolchuk, Newcastle University
  1. Re-exploration of all ATG genes.
  2. Getting PIKy with the lysosome membrane (again).
  3. Autophagic dysregulation triggers innate immune activation in glucocerebrosidase deficiency.
  4. Dual function of the Leon/USP5 deubiquitinase in the ubiquitin-proteasome and autophagic pathways.
  5. Rest, Repair, Repeat: The Complex Relationship of Autophagy and Sleep.
  6. The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  7. Autophagy at the postsynapse begins with Rab11 and does not end with dendritic spine pruning.
  8. mTOR inhibition in Q175 Huntington's disease model mice facilitates neuronal autophagy and mutant huntingtin clearance.
  9. Neuronal activity triggers secretory autophagy to mediate the extracellular release of SNCA/α-synuclein.
  10. Autophagy Process in Parkinson's Disease Depends on Mutations in the GBA1 and LRRK2 Genes.
  11. mTOR and autophagy in acute lung injury pathogenesis and therapeutic potential.
  12. INPP5D inhibits anti-malarial immunity by promoting IRF3 degradation through selective autophagy.
  13. Autophagic degradation of SQSTM1 enables fibroblast activation to accelerate wound healing.
  14. AeiA, an Atg8-interacting protein in Aspergillus oryzae, promotes peroxisome degradation by pexophagy.
  15. Positional specialization of LIR motifs in RavZ and the autophagy-related protein ATG4B.
  16. S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.
  17. Autophagy in plants.
  18. A redox-independent stress response mediated by phase-separated SQSTM1/p62.
  19. The selective autophagic degradation of avian metapneumovirus subgroup C M2-2 protein via SQSTM1 suppresses viral replication.
  20. A novel allosteric GCase modulator prevents Tau accumulation in GBA1WT and GBA1L444P/L444P cellular models.
  21. Ouabain promotes claudin-1, -2, and -4 autophagic degradation through oxidative stress and AMPK activation in MDCK cells.
  22. ATG3 is subjected to redox regulation to quarantee ATG8 lipidation under ROS-generating stresses.
  23. A new role of RAB21 and VARP in autophagy and autophagic exocytosis of ATP.
  24. Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.
  25. The regulation of microglia by aging and autophagy in multiple sclerosis.
  26. ATG5 is dispensable for ATG8ylation of cellular proteins.
  27. Photo-protective role of ATG5/ATG7-independent alternative autophagy in human keratinocytes.
  28. Amino acid storage: lysosomal double role in health and disease.
  29. Autophagy in alzheimer disease pathogenesis and its therapeutic values.
  30. Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.
  31. Autophagy dysfunction and neurodegeneration: Where does it go wrong?
  32. NOD1 deficiency promotes inflammation via autophagic degradation of ASK1.
  33. Tspan9 Exacerbates Cardiac Hypertrophy by Impairing Cardiac Autophagy.
  34. Methods for detection of cardiac glycogen-autophagy.
  35. Discovery of autophagy as a universal mechanism for sex steroid synthesis in human ovary and testis.
  36. Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication.
  37. Identification of a novel mechanism for regulation of the early autophagy machinery assembly by PKA.
  38. Chaperone-mediated autophagy in fish: A key function amid a changing environment.
  39. TMBIM1 promotes epithelial mesenchymal transition by accelerating autophagic degradation of E-cadherin in glioblastoma.
  40. Structural biology of the Atg8 and Atg12 conjugation systems.
  41. Discovery of small-molecule inhibitors for the protein-protein interactions involving ATG5.
  42. TDP-43 Secretion via Extracellular Vesicles Is Regulated by Macroautophagy.
  43. Truncated tau disrupts autophagy and endolysosomal systems.
  44. Role of neuronal fabp in autophagy and amyloid-β pathology in a Drosophila model of Alzheimer disease.
  45. Reversing an agonist into an inhibitor: Development of mTOR degraders.
  46. Mechanistic insights into the interaction between optineurin with RAB8A.
  47. Improved volume CLEM revealed that aberrant phagophores and RB1CC1/FIP200-containing clusters appear surround SQSTM1/p62 aggregates in Atg9a-deficient cells.
  48. ER tubular body: an ER-derived compartment for redirecting autophagy to secretory functions.
  49. GRB2, a protein known for a long time with a new autophagy-regulating function.
  50. Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos.
  51. Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.
  52. The role of autophagy in ischemic brain injury.
  53. PINK1-mediated mitochondrial autophagy protects lens epithelial cells by reducing ROS and apoptosis.
  1. Autophagy Rep. 2024 ;3(1): 2386194
    Re-exploration of all ATG genes.
    Kentaro Furukawa, Tamara Ginevskaia, Tomotake Kanki.
      Most autophagy-related (ATG) genes have been identified and characterized through studies using the budding yeast Saccharomyces cerevisiae. However, there are no studies that comprehensively compare the contribution of each ATG gene to non-selective bulk autophagy and various types of selective autophagy, including the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy, reticulophagy, and pexophagy. Our recent study quantified these types of autophagy in all atg mutants and showed that (i) autophagy is not completely impaired in specific deletants such as lacking the components of the two ubiquitin conjugation-like (UBL) systems, traditionally regarded as essential for autophagy in yeast, and (ii) residual autophagic activity is especially prominent in mutants of the Atg8 UBL system, which display small autophagic body-like vesicles at a low frequency. Alongside these findings, our comprehensive analysis suggested a link between mitophagy and pexophagy, and a differential contribution of Atg proteins to cargo specificity. We discuss how our datasets are useful for future autophagy research. Abbreviations: Ape1: aminopeptidase I; ATG: autophagy related; Cvt: cytoplasm-to-vacuole targeting; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; PI3K: phosphatidylinositol 3-kinase; UBL: ubiquitin conjugation-like.
    Keywords:  Atg8 conjugation system; Autophagy; Cvt pathway; ER-phagy; core autophagy genes; mitophagy; pexophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2386194
  2. Autophagy Rep. 2024 ;3(1): 2412916
    Getting PIKy with the lysosome membrane (again).
    Alison D Klein, Michael Overholtzer.
      Much is still unknown about microautophagy and its regulators. In our recent paper, one such regulator of microautophagy, the lipid kinase PIKfyve, is described. Previously it was found that treating cells with agents like lysomotropic drugs or proton ionophores, which alter lysosomal osmotic potential and pH, leads to a form of microautophagy that selectively degrades transmembrane proteins. Induction of this type of microautophagy is linked to a lysosomal stress response that involves the targeting of macroautophagy proteins, like ATG8s, to the lysosome membrane, through a mechanism called CASM. We found that CASM-induced microautophagy turns over ATG8s and other lysosomal membrane proteins, and requires PIKfyve activity functioning downstream of ATG8 lipidation. The lysosome biogenesis transcription factor TFEB is induced in parallel to microautophagy, in a CASM-dependent, but PIKfyve-independent manner. These findings demonstrate that stressors that engage CASM cause selective turnover by microautophagy that is coordinated with lysosome biogenesis through a mechanism that is separable through PIKfyve.
    Keywords:  ATG8; CASM; LC3; PIKfyve; TFEB; TRPML1; autophagy; lysosome; microautophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2412916
  3. Autophagy Rep. 2024 ;3(1): 2372997
    Autophagic dysregulation triggers innate immune activation in glucocerebrosidase deficiency.
    Magda L Atilano, Alexander J Hull, Kerri J Kinghorn.
      Mutations in the GBA1 (glucosylceramidase beta 1) gene cause the most common lysosomal storage disorder, Gaucher disease (GD), characterized by the lysosomal accumulation of glucosylceramide and lysosomal dysfunction. Downstream of defects in lysosomal-autophagosome fusion, GD cells display autophagic dysfunction. Immune activation and inflammation are also known features of GD pathogenesis. However, the precise link between autophagy and immune activation, and the tissue-specific nature of these pathologies, are yet to be determined. Here we summarize our recent manuscript, which probes the role of autophagy in stimulating a chronic innate immune response in a Drosophila GD model. The gut-brain axis is increasingly being implicated in disease pathology, and accordingly, we demonstrated gastrointestinal dysfunction and gut microbiome dysbiosis in GD flies. Moreover, intestinal cells display lysosomal-autophagic defects like those seen in the GD fly brain. Stimulation of autophagy with rapamycin treatment is sufficient to lower NF- κ B signaling in the gut. Our research suggests that autophagic impairment in GD flies drives microbiome dysbiosis and chronic immune activation, with deleterious consequences on organismal health. We highlight pharmacological activation of autophagy, targeting tissues such as the gut, as a potential therapeutic strategy in GD. Abbreviations AMP, antimicrobial peptide; DAMP, damage associated molecular pattern; GBA1, glucosylceramidase beta 1; LC3, microtubule-associated protein 1 light chain 3; MEGF10, multiple EGF like domains 10; mTOR, mammalian target of rapamycin; PGRP, peptidoglycan recognition protein receptor; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β.
    Keywords:  GBA1; Gaucher disease; Parkinson’s disease; autophagy; glucocerebrosidase; innate immunity; lysosomal
    DOI:  https://doi.org/10.1080/27694127.2024.2372997
  4. Autophagy Rep. 2023 ;2(1): 2278299
    Dual function of the Leon/USP5 deubiquitinase in the ubiquitin-proteasome and autophagic pathways.
    Yuchieh Jay Lin, Guang-Chao Chen.
      The ubiquitin-proteasome system (UPS) and autophagy are highly conserved processes that maintain cellular health through the clearance of misfolded/aberrant proteins and damaged organelles. Ubiquitination is a crucial protein modification to regulate entry in these two pathways. However, the function of deubiquitinases (DUBs) in the UPS and autophagy remains largely unclear. The Leon/USP5 deubiquitinase is essential for maintaining ubiquitin homeostasis and proteasome function. In our recent study, we found that Leon/USP5 depletion resulted in the induction of autophagosome formation and an enhancement of the autophagic flux. Additionally, a genetic analysis in Drosophila revealed that Leon overexpression suppressed Atg1-induced cell death. We further showed that Leon/USP5 interacts with the autophagy initiator Atg1/ULK1, regulating its levels and thus modulating autophagosome formation. These findings suggest that Leon/USP5 plays a dual role in regulation of UPS and autophagy. Abbreviations: Atg1: autophagy-related 1; Atg7: autophagy-related 7; DUB: deubiquitinase; ED: enzyme dead; PTM: post-translational modification; SQSTM1: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; USP5: ubiquitin-specific proteinase 5; WT: wild-type.
    Keywords:  Atg1/ULK1; Leon/USP5; Ref(2)P/SQSTM1; autophagy; deubiquitinase
    DOI:  https://doi.org/10.1080/27694127.2023.2278299
  5. J Mol Biol. 2025 May 21. pii: S0022-2836(25)00293-1. [Epub ahead of print] 169227
    Rest, Repair, Repeat: The Complex Relationship of Autophagy and Sleep.
    Halvor Ullern, Paulina Schnur, Charlotte N Boccara, Helene Knævelsrud.
      Autophagy and sleep are two evolutionary conserved mechanisms across the animal kingdom. Autophagy is a pathway for the degradation of cytoplasmic material in the lysosome, playing important roles in the homeostasis and health of the organism. On the other hand, sleep is a homeostatically regulated state with numerous presumed essential roles, including the restoration of tissue and physiological functions, such as brain waste clearance via the activation of the glymphatic systems. Given that sleep and autophagy are crucial processes tightly linked to homeostasis and maintenance of good health, understanding how they interact is of great interest, especially as sleep quality decreases in our modern 24-hour societies. Autophagy represents a promising target for therapeutic interventions in this context. Here, we review the contrasted and complementary roles of autophagy and sleep in maintaining homeostasis. Specifically, we focus on recent evidence suggesting that sleep impairment may increase autophagy, while autophagosome levels may modulate the amount of sleep. We discuss outstanding questions at the intersection of these two fields, highlighting methodological shortcomings in the current literature. Overcoming these limitations will be instrumental to design new experiments with the aim of answering one of the greatest mysteries of our time - why do we sleep?
    Keywords:  Autophagy; circadian rhythm; homeostasis; macroautophagy; neurosciences; sleep
    DOI:  https://doi.org/10.1016/j.jmb.2025.169227
  6. Autophagy Rep. 2025 ;4(1): 2474796
    The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
    Jimmy Beckers, Philip Van Damme.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two extremes of a neurodegenerative disease spectrum characterised by overlapping genetic, clinical, and neuropathological features. This review covers the intricate relationship between both ALS and FTD and defects in the autophagy and endolysosomal pathway as recent evidence has pointed towards alterations in these pathways as being a root cause of disease pathogenesis. Here, we review the current knowledge on the interplay between ALS/FTD and lysosomebased proteostasis pathways and carefully asses the steps of the autophagy and endolysosomal pathways that are impaired by ALS or FTDcausing variants. Finally, we present a comprehensive overview of therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating the impact of these devastating diseases. Through this review, we aim to enhance the understanding of the pathophysiological mechanisms involving autophagy and/or the endolysosomal system that underlie the ALS-FTD spectrum and underscore the necessity for specific therapeutic approaches that target these shared vulnerabilities.
    Keywords:  Amyotrophic lateral sclerosis (ALS); autophagosome; autophagy; endolysosome; endosome; frontotemporal dementia (FTD); lysosome; neurodegeneration
    DOI:  https://doi.org/10.1080/27694127.2025.2474796
  7. Autophagy Rep. 2024 ;3(1): 2346064
    Autophagy at the postsynapse begins with Rab11 and does not end with dendritic spine pruning.
    Aleksandra Janusz-Kaminska, Jacek Jaworski.
      Neurons are highly differentiated and compartmentalized cells that conduct cellular processes in a spatiotemporally regulated manner. Autophagy in neurons occurs locally under stimulation and contributes to synaptic plasticity. Little is known about the initial steps leading to autophagy upon neuronal stimulation and the role of autophagic compartments at the postsynaptic part of the synapse. Here, we summarize our recent manuscript on Rab11 role in autophagy initiation in the dendritic spines. We showed that Rab11 maintains in the dendritic spines Atg9A and is necessary for LC3+ vesicles to emerge at the postsynapse. We hypothesize that autophagosomes arise due to an interplay between NMDA receptor stimulation and local mTOR kinase activity. We suggest that autophagosomes are not, in fact, responsible for dendritic spine pruning.
    Keywords:  Atg9A; Rab11; autophagy; dendritic spines; mTOR; neurons; synaptic plasticity
    DOI:  https://doi.org/10.1080/27694127.2024.2346064
  8. Elife. 2025 May 20. pii: RP104979. [Epub ahead of print]14
    mTOR inhibition in Q175 Huntington's disease model mice facilitates neuronal autophagy and mutant huntingtin clearance.
    Philip Stavrides, Chris N Goulbourne, James Peddy, Chunfeng Huo, Mala Rao, Vinod Khetarpal, Deanna M Marchionini, Ralph A Nixon, Dun-Sheng Yang.
      Huntington's disease (HD) is caused by the expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting in hallmark aggresomes/inclusion bodies (IBs) composed of mutant huntingtin protein (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance is considered a potential therapeutic strategy for HD. Our recent evaluation of the autophagic-lysosomal pathway (ALP) in human HD brain reveals upregulated lysosomal biogenesis and relatively normal autophagy flux in early Vonsattel grade brains, but impaired autolysosome clearance in late grade brains, suggesting that autophagy stimulation could have therapeutic benefits as an early clinical intervention. Here, we tested this hypothesis by crossing the Q175 HD knock-in model with our autophagy reporter mouse TRGL (Thy-1-RFP-GFP-LC3) to investigate in vivo neuronal ALP dynamics. In the Q175 and/or TRGL/Q175 mice, mHTT was detected in autophagic vacuoles and also exhibited a high level of colocalization with autophagy receptors p62/SQSTM1 and ubiquitin in the IBs. Compared to the robust lysosomal pathology in late-stage human HD striatum, ALP alterations in Q175 models are also late-onset but milder, that included a lowered phospho-p70S6K level, lysosome depletion, and autolysosome elevation including more poorly acidified autolysosomes and larger-sized lipofuscin granules, reflecting impaired autophagic flux. Administration of a mTOR inhibitor to 6-mo-old TRGL/Q175 normalized lysosome number, ameliorated aggresome pathology while reducing mHTT-, p62-, and ubiquitin-immunoreactivities, suggesting the beneficial potential of autophagy modulation at early stages of disease progression.
    Keywords:  Huntington's disease; Q175 mouse model; TRGL mice; autophagy; autophagy modulation; huntingtin; medicine; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.104979
  9. Autophagy Rep. 2024 ;3(1): 2410683
    Neuronal activity triggers secretory autophagy to mediate the extracellular release of SNCA/α-synuclein.
    Yoshitsugu Nakamura, Shigeki Arawaka.
      Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in cellular homeostasis by the formation of a double-membrane autophagosome in concert with numerous ATG (autophagy-related) proteins. However, the mechanism that mediates autophagic secretion is not fully understood. To explore how autophagic secretion is physiologically triggered and regulated in neurons, we investigated whether neuronal activity affected autophagic secretion by analyzing SNCA secretion in mouse primary cortical neurons and SH-SY5Y cells. In primary neurons, rapamycin promoted SNCA secretion, while the effect was canceled in primary neurons of Becn1 +/-deficient mice. Stimulating neuronal activity by glutamate promoted SNCA secretion, autophagic flux, and colocalization of SNCA with LC3 (microtubule-associated proteins 1 light chain 3). These effects were inhibited by the intracellular Ca2+ chelator BAPTA-AM. Additionally, glutamate-induced SNCA secretion was suppressed by Atg5 or Rab8a knockdown in SH-SY5Y cells, and mainly occurred in the fashion associated with extracellular vesicles in primary neurons. These results suggest that neuronal activity triggers autophagic secretion for releasing SNCA via an increase in intracellular Ca2+ concentration.
    Keywords:  SNCA/α-synuclein; extracellular vesicle; neuronal activity; secretory autophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2410683
  10. Biochem Genet. 2025 May 19.
    Autophagy Process in Parkinson's Disease Depends on Mutations in the GBA1 and LRRK2 Genes.
    A I Bezrukova, K S Basharova, A K Emelyanov, A V Rybakov, I V Miliukhina, S N Pchelina, T S Usenko.
      Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and abnormal aggregation of the alpha-synuclein protein. Disruption of the autophagy-lysosomal pathway is closely associated with PD pathogenesis. Here, using western-blot analysis we assessed the level of autophagy-related proteins, including phosphorylated mTOR (p-mTOR), phosphorylated RPS6 (p-RPS6), beclin-1 (BECN1), LC3B, p62, and cathepsin D (CTSD) in macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages) of GBA1-PD (p.N370S/N, p.L444P/N), LRRK2-PD (p.G2019S/N), idiopathic PD (iPD) patients, and healthy controls. Our findings revealed mutation-specific disruptions in autophagy pathways among PD patients. In p.N370S-GBA1-PD, PBMC-derived macrophages exhibited elevated levels of p-RPS6, BECN1, LC3B-II and decreased mature form of CTSD levels suggesting more active mTOR-dependent autophagy initiation alongside potential autophagosome accumulation that may lead to downregulation of lysosomal degradation. p.L444P-GBA1-PD PBMC-derived macrophages showed increased levels of p-RPS6 and BECN1, coupled with decreased p62 levels and stable mature form of CTSD and LC3B-II, indicative of enhanced autophagy flux driven by mTOR activity without evident lysosomal dysfunction. In p.G2019S-LRRK2-PD patients, PBMC-derived macrophages demonstrated elevated p-RPS6, LC3B-II, and mature CTSD levels, alongside reduced p62 levels. These changes suggest higher basal autophagosome abundance in steady-state autophagy and turnover, potentially driven by lysosomal alterations rather than direct mTOR dysregulation. These mutation-dependent differences highlight distinct autophagy dynamics in GBA1-PD and LRRK2-PD, underscoring the critical role of genetic mutations in modulating PD pathogenesis. Our results emphasize the necessity for subtype-specific therapeutic strategies targeting autophagy and other mTOR-regulated pathways to address the heterogeneity of PD mechanisms.
    Keywords:   GBA1 ; LRRK2 ; Autophagy; PBMC-derived macrophages; Parkinson’s disease; mTOR
    DOI:  https://doi.org/10.1007/s10528-025-11125-z
  11. J Thorac Dis. 2025 Apr 30. 17(4): 2679-2692
    mTOR and autophagy in acute lung injury pathogenesis and therapeutic potential.
    Zihan Yi, Jiahao Liu, Lanying Shen, Yue Hu.
      Acute lung injury (ALI) poses a significant clinical challenge due to its high morbidity and mortality rates. Current treatment options are limited in their efficacy, necessitating the exploration of novel therapeutic targets. The mammalian target of rapamycin (mTOR), a crucial regulator of various cellular processes, has been implicated in the pathogenesis of ALI. Autophagy, a tightly regulated cellular degradation process controlled by mTOR, plays a pivotal role in the pathogenesis of ALI and cellular homeostasis. Mounting evidence also suggests that the mTOR pathway and autophagy play crucial roles in the pathogenesis and regulation of ALI. Herein, we reviewed the current understanding of how mTOR signaling and autophagy intersect in the context of ALI, with a focus on their roles across different cell types. This analysis highlights their dual roles in either promoting pulmonary injury or providing protection, depending on the specific cell types and different ALI models. Insights into the intricate balance between mTOR-mediated pathways and autophagic responses provide a foundation for developing targeted therapeutic strategies aimed at alleviating ALI through the modulation of these pathways. This review underscores the therapeutic potential of targeting mTOR and autophagy, presenting innovative and promising approaches for improving the clinical management and outcomes of ALI.
    Keywords:  Acute lung injury (ALI); autophagy; mammalian target of rapamycin (mTOR); pathogenesis; therapeutic potential
    DOI:  https://doi.org/10.21037/jtd-24-1817
  12. Autophagy Rep. 2023 ;2(1): 2254614
    INPP5D inhibits anti-malarial immunity by promoting IRF3 degradation through selective autophagy.
    Hongyu Li, Xiao Yu.
      As a member of the inositol polyphosphate-5-phosphatase family, INPP5D (inositol polyphosphate-5-phosphatase D) is an important regulator of immune cell activation. To date, the mechanisms underlying anti-malarial immunity have not been elucidated. We recently identified INPP5D as a negative regulator of IFN-I (type I interferon) signaling by promoting autophagic degradation of IRF3 (interferon regulatory factor 3) during malaria infection. Mechanistically, INPP5D enhances the association between IRF3 and the autophagy receptor CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2), which promotes the K63-linked ubiquitination of IRF3 at K313 and serves as a signal for CALCOCO2-dependent selective macroautophagy (hereafter autophagy). Moreover, INPP5D is downregulated by IFN-I-induced miR-155-5p after Plasmodium yoelii (P. yoelii) nigeriensis N67 infection and plays a role as a feedback loop between IFN-I signaling and autophagy. Thus, our study reveals the key role of INPP5D in mediating the crosstalk between IFN-I response and autophagy during anti-malarial immune responses, and suggests that INPP5D may be a potential therapeutic target to control malaria. Abbreviations: ATG5; autophagy-related 5; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CQ, chloroquine; INPP5D/SHIP1, inositol polyphosphate-5-phosphatase D; IRF3, interferon regulatory factor 3; IFN-I, type I interferon; 3-MA, 3-methyladenine.
    Keywords:  Anti-malarial immunity; INPP5D; IRF3; selective autophagy; type I interferon
    DOI:  https://doi.org/10.1080/27694127.2023.2254614
  13. Autophagy. 2025 May 21.
    Autophagic degradation of SQSTM1 enables fibroblast activation to accelerate wound healing.
    Yujiao Xu, Xin Gu, Wenshu Li, Boyang Lin, Yiting Xu, Qingcheng Wei, Qingyuan Liu, Yamin Zhao, Rongzhuo Long, Hulin Jiang, Zhaoqiu Wu, Yunyao Liu, Lei Qiang.
      Wound healing is a meticulously coordinated and intricate progression that necessitates precise regulation of fibroblast behavior. Macroautophagy/autophagy is a degradation system for clearing damaged cellular components. SQSTM1/p62 (sequestosome 1), a well-established autophagy receptor, also functions as a signaling hub beyond autophagy. Here, we observed a significant upregulation of autophagy in fibroblasts after wounding. Using mice with fibroblast-specific deletion of Atg7 (autophagy related 7), we found that fibroblast autophagy governed wound healing. Fibroblast autophagy deficiency delayed proper dermal repair that was mired in insufficient fibroblast proliferation, migration, and myofibroblast transition. In vitro experiments further revealed that autophagy deficiency disrupted TGFB1 (transforming growth factor beta 1)-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, autophagy deficiency led to SMAD2 (SMAD family member 2) and SMAD3 sequestration within SQSTM1 bodies and attenuated TGFB1-induced receptor-regulated SMAD (R-SMAD) phosphorylation in an SQSTM1-dependent manner. Furthermore, sqstm1 deletion rescued the delayed skin wound healing caused by autophagy deficiency, and autophagy inducers promoted wound healing in an SQSTM1-dependent manner. Our findings highlight the critical role of fibroblast autophagy in wound healing and elucidate the underlying mechanisms by which autophagy regulates fibroblast behavior.
    Keywords:  Autophagy; SMAD; SQSTM1; TGFB; fibroblast; wound healing
    DOI:  https://doi.org/10.1080/15548627.2025.2508546
  14. Autophagy Rep. 2023 ;2(1): 2271281
    AeiA, an Atg8-interacting protein in Aspergillus oryzae, promotes peroxisome degradation by pexophagy.
    Takashi Kikuma, Joichiro Nishio.
      There are two types of autophagy, non-selective (bulk) autophagy, in which substrates are randomly incorporated into autophagosomes, and selective autophagy, in which substrates are specifically targeted. In filamentous fungi, the molecular mechanism underlying selective autophagy remains largely unknown. Recently we identified a novel protein, AoAtg8-interacting protein A (AeiA), in the filamentous fungus Aspergillus oryzae. AeiA was localized to peroxisomes and autophagosomal intermediates, such as phagophore assembly site (PAS) and the phagophore. Moreover, pexophagy flux was reduced in AeiA deletants. Taken together, AeiA is a novel selective autophagy-related protein that contributes to pexophagy in A. oryzae. Our findings provide insight into the molecular mechanisms of selective autophagy including pexophagy in filamentous fungi. Abbreviations: AIM, Atg8-family interacting motifs; Atg8, autophagy-related 8; EGFP, enhanced green fluorescent protein; GABARAP, Gamma aminobutyric acid A receptor associated protein; LC3, Microtubule-associated protein light chain 3; MTS, microbody targeting signal; PD, potato dextrose.
    Keywords:  Aspergillus oryzae; Atg8; filamentous fungi; peroxisome; pexophagy
    DOI:  https://doi.org/10.1080/27694127.2023.2271281
  15. Autophagy Rep. 2025 ;4(1): 2438563
    Positional specialization of LIR motifs in RavZ and the autophagy-related protein ATG4B.
    Sang-Won Park, Jin-A Lee, Deok-Jin Jang.
      LC3-interacting region (LIR) motifs are essential for recruiting proteins onto autophagosomes, the hallmark of autophagy. We recently explored the relevance of the specific position of the LIRs in RavZ and ATG4B (autophagy-related 4B). RavZ's N-terminal LIRs drive substrate recognition and enzymatic activity, while its C-terminal LIR aids membrane localization. In contrast, ATG4B's C-terminal LIR is indispensable for LC3B (microtubule-associated protein 1 light chain 3B)-phosphatidylethanolamine (PE) delipidation on autophagosomes but not required for cytosolic LC3B priming, which is mediated solely by its catalytic domain (CAD). These findings underscore the structural adaptation of LIRs for context-specific functions. This novel nuanced understanding provides a framework for developing therapeutic tools to modulate autophagy by precisely targeting LIRs or their associated processes, offering potential treatment for diseases like neurodegenerative disorders and infections characterized by autophagy dysregulation.
    Keywords:  ATG4B; Autophagy; LC3/GABARAP; LIR; RavZ; delipidation
    DOI:  https://doi.org/10.1080/27694127.2024.2438563
  16. Autophagy. 2025 May 20.
    S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.
    Fan Xia, Weining Li, Wenru Wang, Jiru Liu, Xiaolin Li, Jing Cai, Hao Shan, Zhe Cai, Jun Cui.
      Macroautophagy (hereafter autophagy), a major intracellular catabolic process, is evolutionarily conserved from yeasts to mammals, and is associated with a broad range of human diseases. Autophagy is morphologically characterized by the formation of double-membrane autophagosomes. ATG9A, a multi-spanning transmembrane protein and lipid scramblase, is a core component of the autophagy machinery that complements membrane sources and equilibrates lipids across membrane bilayers. Here, we report that palmitoyltransferase ZDHHC5 is indispensable for autophagosome nucleation and subsequent autophagosome formation. Upon autophagy induction, ZDHHC5 is internalized from the plasma membrane into intracellular compartments via clathrin-mediated endocytosis. This enzyme activates ATG9A S-palmitoylation at cysteine 155/156, which orchestrates the interaction of ATG9A with the heterotetrameric adaptor protein complex family member AP4E1/AP-4ε and subsequent trafficking from the trans-Golgi network to endosomal compartments. Functionally, impairment of ATG9A S-palmitoylation results in defects in autophagy initiation and autophagosome formation. These findings identify a regulatory mechanism that coordinates ATG9A-binding with AP4E1 and vesicular trafficking events through ATG9A S-palmitoylation by ZDHHC5, thereby ensuring the spatiotemporal fidelity of membrane trafficking and maintenance of autophagic homeostasis.
    Keywords:  AP4E1; Trans-golgi network; ZDHHC5; autophagosome formation; clathrin-mediated endocytosis; membrane trafficking
    DOI:  https://doi.org/10.1080/15548627.2025.2509376
  17. Autophagy Rep. 2024 ;3(1): 2395731
    Autophagy in plants.
    Morten Petersen, Tamar Avin-Wittenberg, Diane C Bassham, Yasin Dagdas, Chudi Fan, Alisdair R Fernie, Liwen Jiang, Divya Mishra, Marisa S Otegui, Eleazar Rodriguez, Daniel Hofius.
      Autophagy is a process of cellular self-eating, which allows organisms to eliminate and recycle unwanted components and damaged organelles to maintain cellular homeostasis. It is an important process in the development of eukaryotic organisms. Autophagy plays a critical role in many physiological processes in plants such as nutrient remobilization, cell death, immunity, and abiotic stress responses. Autophagy thus represents an obvious target for generating resilient crops. During plant development, autophagy is also implicated in the differentiation and maturation of various cell types and plant organs, including root cap cells, tracheary elements, gametes, fruits and seeds. Here, we review our current understanding and recent advances of plant autophagy including insight into autophagy regulation and signaling as well as autophagosome membrane biogenesis. In addition, we describe how autophagy contributes to development, metabolism, biotic and abiotic stress tolerance and where the autophagic field is heading in terms of applied research for crop improvement.
    Keywords:  Plant autophagy; cargo receptors; crop improvement; development; endomembrane trafficking; immunity; metabolism; quality control; regulation and signalling; stress tolerance
    DOI:  https://doi.org/10.1080/27694127.2024.2395731
  18. Autophagy Rep. 2024 ;3(1): 2383088
    A redox-independent stress response mediated by phase-separated SQSTM1/p62.
    Yoshinobu Ichimura, Masaaki Komatsu.
      The KEAP1 (kelch like ECH associated protein 1)- NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2) pathway is a major antioxidative stress pathway that contributes to cellular homeostasis. KEAP1 acts as a sensor and attenuates degradation of the transcription factor NRF2, which induces gene expression for a network of enzymes involved in the antioxidant response. When cells are exposed to various electrophiles and reactive oxidative species, they modify one or more selective cysteine residues in KEAP1, resulting in conformational changes that disable its NRF2-inhibitory function. In addition to this redox-dependent pathway, SQSTM1/p62 (sequestosome 1), which is a selective autophagy receptor for ubiquitinated proteins and a driver of liquid-liquid phase separation (LLPS) upon binding to ubiquitinated proteins, competitively inhibits the binding between KEAP1 and NRF2, thereby disabling the NRF2-repressive function of KEAP1. Our study showed that phase-separated SQSTM1/p62 bodies are phosphorylated by ULK1 (Unc-51 like autophagy activating kinase 1) and that KEAP1 is retained in the SQSTM1/p62 body, resulting in NRF2-activation in a redox-independent manner.
    Keywords:  Autophagy; KEAP1; LLPS; NRF2; p62
    DOI:  https://doi.org/10.1080/27694127.2024.2383088
  19. Autophagy Rep. 2024 ;3(1): 2375936
    The selective autophagic degradation of avian metapneumovirus subgroup C M2-2 protein via SQSTM1 suppresses viral replication.
    Lei Hou, Jinshuo Guo, Jianwei Zhou, Jue Liu.
      Avian metapneumovirus subgroup C (aMPV/C) is an emerging pathogen that causes acute respiratory infection in chickens and turkeys. Sequestosome 1 (SQSTM1), a selective autophagy receptor, regulates cellular activity or viral replication by recognizing ubiquitinated substrates. Here, we found that SQSTM1 expression inhibits aMPV/C replication through selective autophagy. In particular, SQSTM1 interacts with the aMPV/C M2-2 protein via its PB1 domain, and by recognizing a ubiquitinated lysine at position 67 of viral M2-2 protein. This recognition leads to the autophagic degradation of the aMPV/C M2-2 protein, suppressing viral replication.
    Keywords:  M2-2 protein; SQSTM1; aMPV/C; degradation; selective autophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2375936
  20. Sci Rep. 2025 May 21. 15(1): 17646
    A novel allosteric GCase modulator prevents Tau accumulation in GBA1WT and GBA1L444P/L444P cellular models.
    Matteo Ciccaldo, Natàlia Pérez-Carmona, Ester Piovesana, Sara Cano-Crespo, Ana Ruano, Aida Delgado, Ilaria Fregno, Beatriz Calvo-Flores Guzmán, Manolo Bellotto, Maurizio Molinari, Joanne Taylor, Stéphanie Papin, Ana María García-Collazo, Paolo Paganetti.
      A slow decline in the autophagy-lysosomal pathway is a hallmark of the normal aging brain. Yet, an acceleration of this cellular function may propel neurodegenerative events. In fact, mutations in genes associated with the autophagy-lysosomal pathway can lead to Parkinson's disease. Also, amyloidogenic protein deposition is observed in lysosomal storage disorders, which are caused by genetic mutations representing risk factors for Parkinson's disease. For example, Gaucher's disease GBA1 mutations leading to defects in lysosomal sphingolipid metabolism cause α-synuclein accumulation. We observed that increased lysosomal Tau accumulation is found in human dermal fibroblasts engineered for inducible Tau expression. Inhibition of the GBA1 product GCase augmented Tau-dependent lysosomal stress and Tau accumulation. Here, we show increased Tau seed-induced Tau accumulation in Gaucher's fibroblasts carrying GBA1 mutations when compared to normal fibroblasts. Pharmacological enhancement of GCase reversed this effect, notably, also in normal fibroblasts. This suggests that boosting GCase activity may represent a therapeutic strategy to slow down aging-dependent lysosomal deficits and brain protein deposition.
    DOI:  https://doi.org/10.1038/s41598-025-02346-8
  21. Autophagy Rep. 2023 ;2(1): 2256146
    Ouabain promotes claudin-1, -2, and -4 autophagic degradation through oxidative stress and AMPK activation in MDCK cells.
    Jessica P Campos-Blázquez, Catalina Flores-Maldonado, Juan M Gallardo, José Bonilla-Delgado, Alan A Pedraza-Ramírez, Octavio López-Méndez, Enoc M Cortés-Malagón, Rubén G Contreras.
      Epithelial cells transport substances through the cellular and paracellular pathways. The last one depends on tight junctions, particularly on claudins, the family of integral membrane proteins responsible for the permeability and selectivity of these junctions. 300 nM ouabain (OUA) induces endocytosis and lysosomal degradation of claudin-2 and -4 in an Src and ERK1/2 kinases-dependent manner. Here we investigate whether OUA-induced lysosomal degradation of claudins implicates autophagy in renal epithelial Madin-Darby canine kidney cells. During autophagy, LC3 protein binds phosphatidylethanolamine and incorporates, together with protein p62, into the phagophore. Subsequently, the autolysosome degrades both LC3 and p62 proteins. OUA's occupancy of its site in the Na⁺/K⁺ATPase (300 nM, 10 h) increases autophagic flux because of degradation of LC3 and p62 and an increase in the number of autophagosomes, as detected by fluorescent LC3 and p62 puncta and the rise in autolysosomes seen by the GFP-LC3-RFP probe. Finally, OUA increases the colocalisation of claudin-1, -2, or -4 with p62 in these puncta. OUA induces autophagy increasing reactive oxygen species generation that activates AMP-activated protein kinase, phosphorylating ULK1 at S555. The autophagy inducer rapamycin causes a degradation of the studied claudins comparable to the one generated by OUA. Furthermore, the autophagy inhibitor dorsomorphin blocks OUA-induced autophagy and claudin-1, -2, and -4 degradation. These results demonstrated that OUA induces claudin-1, -2, and -4 autophagy through oxidative stress. Abbreviations: AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: Adenosine triphosphate; DM: dorsomorphin; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LC3: microtubule-associated protein 1A/1B-light chain 3; MDCK: Madin-Darby canine kidney; mTOR: mammalian target of rapamycin; NAC: N-acetylcysteine; OUA: ouabain; PCC: Pearson's correlation coefficient; PE: phosphatidylethanolamine, Rapa: rapamycin; ROS: reactive oxygen species; SNK: Student-Newman-Keuls; TER: transepithelial electrical resistance; TJs: tight junctions; ULK1: Unc-51-like kinase 1.
    Keywords:  Epithelia; LC3; TER; ULK1; p62; rapamycin; reactive oxygen species; tight junctions
    DOI:  https://doi.org/10.1080/27694127.2023.2256146
  22. Autophagy Rep. 2024 ;3(1): 2300622
    ATG3 is subjected to redox regulation to quarantee ATG8 lipidation under ROS-generating stresses.
    Manuel J Mallén-Ponce, María Esther Pérez-Pérez.
      The conjugation of ATG8 (autophagy-related 8) proteins to the lipid phosphatidylethanolamine (PE) is the result of the coordinated and highly regulated action of several ATG core proteins, including ATG4 proteases and the E1 (ATG7)- and E2 (ATG3)- activating enzymes. Although it has been stablished that ROS signaling plays an important role in autophagy activation, the molecular mechanisms underlying the redox control of ATG proteins remain largely unclear. We have recently shown that ATG3 activity in Chlamydomonas reinhardtii is subjected to reversible redox regulation to ensure ATG8 lipidation and autophagy progression under ROS-linked stress conditions. Abbreviations: ATG, Autophagy-related; Cys, Cysteine; DTTred, Reduced Dithiothreitol; MM(PEG24), Methyl Polyethylene Glycol Maleimide; NEM: N-ethylmaleimide; PE, Phosphatidylethanolamine; ROS, Reactive Oxygen Species; TOR, Target Of Rapamycin; Trx, Thioredoxin; WT, Wild Type.
    Keywords:  ATG3; ATG8 lipidation; Chlamydomonas; ROS; Trx; redox; stress; yeast
    DOI:  https://doi.org/10.1080/27694127.2023.2300622
  23. Autophagy Rep. 2025 ;4(1): 2501365
    A new role of RAB21 and VARP in autophagy and autophagic exocytosis of ATP.
    María Carolina Barbosa, Pablo Reta, Sébastien Nola, Milton Osmar Aguilera, Thierry Galli, María Isabel Colombo, Claudio Marcelo Fader.
      Autophagy has been implicated in various cellular processes, including non-conventional secretion. Our previous findings suggest that ATP is loaded into amphisomes and secreted upon autophagy stimulation at focal adhesion sites in a VAMP7-dependent manner. Here, we demonstrate that the knockout (KO) of VAMP7, along with its partners RAB21 and its guanine nucleotide exchange factor (GEF) VARP, inhibits ATP release, indicating a key role for this pathway in amphisome secretion. Constitutively inactive RAB21 also inhibited ATP secretion. RAB21 overexpression rescued starvation-induced ATP secretion in RAB21 KO, but not in VAMP7 or VARP KO cells. RAB21-LC3-positive vesicles redistributed to the cell periphery upon starvation. KO cells and overexpression experiments showed that RAB21 plays a positive role in autophagosome biogenesis, particularly in controlling the number of LC3-II- and DFCP1-positive structures upon starvation, suggesting a role in the early steps of autophagosome formation. Accordingly, VARP partially colocalized with LC3 upon starvation. Together, these findings identify a novel role for RAB21 in regulating autophagic ATP secretion likely in amphisome biogenesis and their localization in the cell periphery.
    Keywords:  ATP release; LC3; RAB proteins; VAMP7; macroautophagy; secretory autophagy
    DOI:  https://doi.org/10.1080/27694127.2025.2501365
  24. Glia. 2025 May 22.
    Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.
    Nirma D Perera, Subhavi De Silva, Doris Tomas, Brittany Cuic, Bradley J Turner.
      Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1G93A mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.
    Keywords:  ALS; SOD1; SOD1G93A; astrocytes; autophagy; microglia; oligodendrocytes
    DOI:  https://doi.org/10.1002/glia.70045
  25. Pharmacol Res. 2025 May 19. pii: S1043-6618(25)00211-7. [Epub ahead of print] 107786
    The regulation of microglia by aging and autophagy in multiple sclerosis.
    Xiying Wang, Ye Sun, Haojun Yu, Chunran Xue, Xuzhong Pei, Yi Chen, Yangtai Guan.
      Multiple sclerosis (MS) is an inflammatory disease that is often characterized by the development of irreversible clinical disability. Age is a strong risk factor that is strongly associated with the clinical course and progression of MS. Several lines of evidence suggest that with aging, microglia have an aging-related gene expression signature and are close to disease-associated microglia (DAM), which exhibit decreased phagocytosis but increased production of inflammatory factors. The gene expression signatures of microglia in MS overlap with those in aging, inflammation and DAM. Moreover, the clearance of damaged myelin by microglia is impaired in the aged brain. Autophagy is a cellular process that decreases in activity with age. In this review, we provide an overview of the role of autophagy and aging in MS. We describe the impact of autophagy and aging on microglial activation in MS and the molecules involved in autophagy and aging, which are related to the phagocytosis and activation of microglia. We propose that a decrease in autophagy in microglia occurs with aging, leading to a decrease in phagocytosis. Decreases in phagocytosis and increases in the production of inflammatory factors by microglia contribute to chronic inflammation in the aged brain and disease progression in MS. Thus, the modulation of autophagy in microglia serves as a potential therapeutic target for MS.
    Keywords:  aging; autophagic targets in multiple sclerosis; autophagy; microglia; multiple sclerosis
    DOI:  https://doi.org/10.1016/j.phrs.2025.107786
  26. Autophagy Rep. 2024 ;3(1): 2392450
    ATG5 is dispensable for ATG8ylation of cellular proteins.
    Robin Ketteler, Koshiro Kiso, Lucas von Chamier, Alexander Agrotis.
      Protein ATG8ylation refers to a post-translational modification involving covalent attachment of ubiquitin-like autophagy-related protein ATG8 (LC3/GABARAP) to other cellular proteins, with reversal mediated by ATG4 proteases. While lipid ATG8ylation is important for autophagosome formation and mechanistically well-characterized, little is known about the mechanism of protein ATG8ylation. Here, we investigated the conjugation machinery of protein ATG8ylation in CRISPR/Cas9-engineered knockout human cell lines, utilizing a deconjugation-resistant (Q116P G120) form of MAP1LC3B. We report that protein ATG8ylation requires the E1-like activating enzyme ATG7 and E2-like conjugating enzyme ATG3, in common with ATG8 lipidation. However, in contrast, the E3-like ATG12-ATG5-ATG16L1 complex involved in lipidation is dispensable for protein ATG8ylation, since ATG5 knockout cells can form ATG8ylated protein conjugates. Further, we uncover that ATG7 itself is a target of ATG8ylation. Overall, our work provides crucial insight into the mechanism of protein ATG8ylation, distinguishing it from ATG8 lipidation, which will aid investigating its functional role.
    Keywords:  ATG3; ATG4B; ATG7; LC3/GABARAP; LC3ylation; autophagy; conjugating; deconjugation; post-translational modification; ubiquitin-like
    DOI:  https://doi.org/10.1080/27694127.2024.2392450
  27. Autophagy Rep. 2024 ;3(1): 2396212
    Photo-protective role of ATG5/ATG7-independent alternative autophagy in human keratinocytes.
    Tatsuya Hasegawa, Masaya Nakashima, Satoru Torii, Shinya Honda, Shigeomi Shimizu.
      Excessive exposure to sunlight, especially to ultraviolet B (UVB), results in DNA damage and a cutaneous inflammatory reaction commonly known as sunburn, which increases skin cancer risks. UVB-induced inflammasome activation in epidermal keratinocytes mediates the cutaneous inflammatory response, but the intracellular machinery that maintains skin homeostasis by suppressing UVB-induced inflammasome activation is unclear. Here, we summarize our recent work on the protective role of alternative autophagy against UVB-induced NLRP3 (NLR family pyrin domain containing 3) inflammasome activation in human keratinocytes. We found that UVB radiation induces ATG5/ATG7-independent alternative (noncanonical) autophagy, which leads to suppression of NLRP3 inflammasome activation through the clearance of damaged mitochondria in UVB-irradiated keratinocytes. Our findings indicate that ATG5/ATG7-independent alternative autophagy, rather than conventional autophagy, may play a key role in mitigating inflammatory responses, and restoring skin homeostasis after UV radiation.
    Keywords:  Alternative autophagy; GOMED; NLRP3; UV; inflammasome; keratinocyte; mitochondria; skin; sunburn
    DOI:  https://doi.org/10.1080/27694127.2024.2396212
  28. Autophagy Rep. 2025 ;4(1): 2498324
    Amino acid storage: lysosomal double role in health and disease.
    Aiswarya Raj, Samantha Shrihari, Urmi Bandyopadhyay.
      Cellular homeostasis depends on a multitude of cellular functions, which in turn depend on the clearance of damaged components for their maintenance. Lysosomes being one of the main sites of recycling, are at the frontline for cellular protein degradation, which leads to generation of protein building blocks, the amino acids (AAs), within the lysosomal lumen. However, the fate of these lysosomal pool of AAs are only partly known. Recently, studies from our and other groups have led to the finding that AA can be stored in lysosomes and revealed a homeostatic communication of these storages with the environment. Thus, lysosome appear to be a nutritional signaling hub that has a dual role. As a degradation-competent hydrolytic sack, lysosomes have a long-studied degradative function, additionally now they can either store or channel into utilization of the AAs generated through their proteolytic activity. Since the existence of a lysosomal AA storage pool has been determined by changing the levels of extracellular AAs, this indicates a multi-directional homeostatic communication between the lysosome and the extracellular environment. This Lysosomal homeostatic and adaptive response to the niche could be vital for life-threatening age-related degenerative disorders, where the lysosome-autophagy pathway and the microenvironmental cues play major roles in the disease progression, which will be discussed further in this piece.
    Keywords:  Extracellular Environment; LAMTOR-RAG GTPase complex; Lysosome; leucine; nutrient storage
    DOI:  https://doi.org/10.1080/27694127.2025.2498324
  29. Autophagy Rep. 2025 ;4(1): 2471677
    Autophagy in alzheimer disease pathogenesis and its therapeutic values.
    Gabrielle Angst, Nuo Jia, Luis E Tron Esqueda, Yanbo Fan, Qian Cai, Chenran Wang.
      Alzheimer disease (AD) is the most common form of dementia with hallmarks of β-amyloid deposits, neurofilament tangles, synaptic loss and neuronal death in the patient's brain. AD is a heavy burden in an ageing society as there are no effective therapies in treating the causes or slowing down its progression. Autophagy is a conserved process through formation of double membrane structure, namely autophagosome which is delivered to lysosome to digest cellular disposals. Autophagy maintains homoeostasis in the brain and is generally considered to protect brain functions against ageing. The first evidence of autophagy involvement in AD is that there is decreased expression of autophagy essential genes in post-mortem AD brains. Autophagy is also believed to be protective in neurodegeneration. However, the molecular and cellular mechanisms for dysfunction of autophagy in AD are not fully understood. Recent studies of autophagy regulation in AD cover the findings not only in neurons, but also from fast growing evidence for their importance in glia and brain vascular system. Thus, this review composes pertinent information regarding the involvement of autophagy in neurons, glias (including microglia, astrocyte, and oligodendrocyte), and brain vascular cells in AD, and their unique cellular mechanisms of this connection in AD pathology. We will provide effectual insights both in investigating autophagy in AD pathological mechanisms and in establishing a strategic approach for developing autophagy-based AD therapies.
    Keywords:  Alzheimer disease; amyloid-β; autophagy; blood-brain-barrier; glia; neurofilament tangles; neuroinflammation; neuron
    DOI:  https://doi.org/10.1080/27694127.2025.2471677
  30. Autophagy Rep. 2024 ;3(1): 2314361
    Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.
    Rebeca Martín-Jiménez, Olivier Lurette, Etienne Hebert-Chatelain.
      Accumulation of Lewy bodies in dopaminergic neurons is associated to Parkinson disease (PD). The main component of Lewy bodies appears to be aggregates of alpha-synuclein (α-syn). Several mutations of the gene encoding this protein promote its aggregation. Thus, clustering of α-syn is considered a central event in the onset of PD. An old theory also postulates that mitochondrial dysfunction represents another cause of PD pathogenesis. However, the impact of α-syn aggregates on mitochondria remains poorly understood considering the technical difficulties to discriminate between the different forms of α-syn. In this punctum, we describe our recent work in which we used a newly developed optogenetic tool to control the aggregation of α-syn and examine the impact on mitochondria. This work revealed that α-syn aggregates dynamically interact with mitochondria, triggering their depolarization and leading to cardiolipin translocation to the surface of mitochondria and mitophagy. Abbreviations: α-syn: alpha-synuclein; BNIP3L: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; FUNDC1: FUN14 domain-containing protein 1; IMM: inner mitochondrial membrane; LIPA: light-induced protein aggregation; OMM: outer mitochondrial membrane; PD: Parkinson disease; SNc: substantia nigra par compacta.
    Keywords:  Lewy bodies; PLSCR3; mitochondrial fission; mitochondrial membrane potential; parkinson disease; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1080/27694127.2024.2314361
  31. J Mol Biol. 2025 May 16. pii: S0022-2836(25)00285-2. [Epub ahead of print] 169219
    Autophagy dysfunction and neurodegeneration: Where does it go wrong?
    Daphne Oettinger, Ai Yamamoto.
      An infamous hallmark of neurodegenerative diseases is the accumulation of misfolded or unfolded proteins forming inclusions in the brain. The accumulation of these abnormal structures is a mysterious one, given that cells devote significant resources to integrate complementary pathways to ensure proteome integrity and proper protein folding. Aberrantly folded protein species are rapidly targeted for disposal by the ubiquitin-proteasome system (UPS), and even if this should fail, and the species accumulates, the cell can also rely on the lysosome-mediated degradation pathways of autophagy. Despite the many safeguards in place, failure to maintain protein homeostasis commonly occurs during, or preceding, the onset of disease. Over the last decade and a half, studies suggest that the failure of autophagy may explain the disruption in protein homeostasis observed in disease. In this review, we will examine how the highly complex cells of the brain can become vulnerable to failure of aggregate clearance at specific points during the processive pathway of autophagy, contributing to aggregate accumulation in brains with neurodegenerative disease.
    Keywords:  Neurodegeneration; Protein aggregation; glia; neurons; protein homeostasis
    DOI:  https://doi.org/10.1016/j.jmb.2025.169219
  32. Commun Biol. 2025 May 21. 8(1): 781
    NOD1 deficiency promotes inflammation via autophagic degradation of ASK1.
    Yoshitaka Kimura, Miyako Kimura, Noriko Miura, Yusuke Yoshino, Hajime Kono.
      Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a pattern recognition receptor of bacterial peptidoglycans. NOD1 facilitates the elimination of invading intracellular bacteria via autophagy induction. Here, we demonstrate that NOD1 exerts an anti-inflammatory effect mediated via the selective autophagy of host cell protein. In our study of Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis, which is a mouse model of Kawasaki disease, we observed an exacerbated disease phenotype in NOD1-deficient mice. NOD1 deficiency induced a higher expression of inflammatory cytokines via CAWS and CAWS-induced endoplasmic reticulum (ER) stress in bone marrow-derived dendritic cells. Furthermore, exaggerated inflammation was dependent on apoptosis signal-regulated kinase 1 (ASK1). Notably, NOD1 directly interacted with ASK1, inducing selective autophagy of ASK1, which was dependent on ATG16L1, and thus competitively inhibiting ER stress-dependent ASK1 activation. Altogether, these results show that NOD1 modulates excessive inflammatory responses through the upregulation of autophagy.
    DOI:  https://doi.org/10.1038/s42003-025-08213-6
  33. FASEB J. 2025 May 31. 39(10): e70670
    Tspan9 Exacerbates Cardiac Hypertrophy by Impairing Cardiac Autophagy.
    Shushu Jiang, Shichen Bu, Xiang Kang, Yin Dong, Long Chen, Lin Yuan, Menghao Shi, Meng Du, Minglu Liang, Kai Huang, Liu Yang.
      Pathological cardiac hypertrophy leads to heart failure. In this study, we aimed to explore the role of transmembrane protein Tspan9 in the development of cardiac hypertrophy and failure. We found that Tspan9 was upregulated in the hearts of patients with hypertrophic cardiomyopathy (HCM), in the hearts of mice subjected to transverse aortic constriction (TAC), as well as in phenylephrine-induced hypertrophic neonatal rat cardiomyocytes (NRCMs). AAV9-mediated overexpression (OE) of Tspan9 in mouse hearts augmented TAC-induced cardiac hypertrophy and failure, while Tspan9 knockdown (KD) alleviated this effect. Tspan9-OE promotes PE-induced cardiomyocyte enlargement, whereas Tspan9-KD suppresses it. Mechanistically, we demonstrated that Tspan9 interacts with p62, a pivotal regulator of autophagy, impairs its cargo function, leading to autophagy suppression. Remarkably, the anti-hypertrophic effect of Tspan9-KD was impaired when autophagy was inactivated or p62 was knocked down. These findings suggest that Tspan9 exacerbates pressure overload-induced pathological cardiac hypertrophy and failure by suppressing cardiac autophagy through its interaction with p62.
    Keywords:  Tspan9; autophagy; cardiac hypertrophy; heart failure; p62
    DOI:  https://doi.org/10.1096/fj.202500150R
  34. Autophagy Rep. 2024 ;3(1): 2405331
    Methods for detection of cardiac glycogen-autophagy.
    Parisa Koutsifeli, Lorna J Daniels, Joshua Neale, Sarah Fong, Upasna Varma, Marco Annandale, Xun Li, Yohanes Nursalim, James R Bell, Kate L Weeks, Aleksandr Stotland, David J Taylor, Roberta A Gottlieb, Lea M D Delbridge, Kimberley M Mellor.
      Glycogen-autophagy ('glycophagy') is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.
    Keywords:  Atg8; GABARAPL1; autophagy; glycogen; glycophagy flux
    DOI:  https://doi.org/10.1080/27694127.2024.2405331
  35. Autophagy Rep. 2023 ;2(1): 2251804
    Discovery of autophagy as a universal mechanism for sex steroid synthesis in human ovary and testis.
    Yashar Esmaeilian, Francesko Hela, Gamze Bildik, Ece İltumur, Sevgi Yusufoglu, Kayhan Yakin, Ozgur Oktem.
      We recently discovered that lipophagy is a key mechanism to provide free cholesterol required for steroid biosynthesis in human ovary and testis. Pharmacological or genetic inhibition of autophagy by silencing of the autophagy-related (ATG) genes BECN1 (BECLIN1) and ATG5 resulted in a significant reduction in basal and gonadotropin-stimulated estradiol, progesterone (P4) and testosterone production in the ex-vivo explant tissue and cell culture models for ovary and testis. We also described a new mechanism of action for gonadotropin hormones, i.e., follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG)/luteinizing hormone (LH), in this process. They augment the production of sex steroid hormones by upregulating the expression of ATG genes, the accelerating autophagic flux and promoting LDs sequestration into autophagosomes and degradation in lysosomes. Furthermore, we detected several molecular aberrations at different steps of lipophagy-dependent P4 production in the ovary of women with defective luteal function. Our findings might have important clinical implications by opening a new avenue for the understanding and treatment of a wide range of diseases varying from reproductive disorders to sex hormone-producing neoplasms and hormone dependent malignancies, such as carcinomas of breast, endometrium, and prostate. Abbreviations: ACAT, Acyl-coenzyme A-cholesterol-acyl-transferase; AMBRA1, autophagy and beclin 1 regulator 1; ATG, autophagy-related; BECN1, BECLIN1; hCG, human chorionic gonadotropin; E2, estradiol; FSH, follicle stimulating hormone; GABARAP, GABA type A receptor-associated protein; GCs, luteinized granulosa cells; IVF, in vitro fertilization; LAMP2A, lysosomal associated membrane protein 2A; LDs, lipid droplets; LDLs, low-density lipoproteins; P4: progesterone; PCOS, polycystic ovary syndrome; SOAT1: Sterol-O-acetyltransferase; MAP1LC3B, microtubule associated protein 1 light chain 3 beta; PLIN3, perilipin 3; STAR, steroidogenic acute regulatory protein; SQSTM1, sequestosome-1.
    Keywords:  Autophagy; gonadotropins; human; luteal phase defect; ovary; sex steroids; steroidogenesis; testis
    DOI:  https://doi.org/10.1080/27694127.2023.2251804
  36. FASEB J. 2025 May 31. 39(10): e70659
    Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication.
    Xiaoyan Tian, Meng Yuan, Linrun Li, Deyan Chen, Bingxin Liu, Xue Zou, Miao He, Zhiwei Wu.
      Enterovirus 71 (EV71) infection poses a global public health challenge, especially in infants and young children, with severe cases leading to fatal consequences. EV71 infection modulates various biological processes of the host and evades host immunity through multiple mechanisms. The balance of mitochondrial dynamics is important for cellular homeostasis. However, the mechanisms underlying EV71-induced cellular damage via mitophagy remain unclear. In the current study, we showed that EV71 infection significantly reduced the total and mitochondrial ATP contents in cells, as well as the expression of mitochondrial proteins TOM20 and TIM23. Then, EV71 infection increased the protein levels of PINK1, Parkin, and LC3B, suggesting that EV71 infection triggers the mitophagy. Silencing PINK1 caused a significant reduction in viral replication, while overexpressing Parkin promoted the replication of EV71. Moreover, CsA treatment, as a mitophagy inhibitor, alleviated pathological damage and suppressed the replication of EV71 in vivo. Mechanistic study showed that silencing PINK1 inhibited the cleavage of MAVS by EV71, while overexpressing Parkin enhanced the cleavage of MAVS by EV71, suggesting that PINK1-mediated mitophagy was involved in regulating innate immunity. Furthermore, we found that EV71 infection promoted the release of mitochondria carrying EV71 virions into the extracellular environment, which mediated infection of other cells, thus facilitating virus spreading. In addition, we also demonstrated that the extracellular mitochondria induced the degradation of MAVS and mitophagy promoted the release of mitochondria in EV71-infected HeLa cells. In conclusion, these findings suggest that EV71 infection induces PINK1-mediated mitophagy, which inhibits innate immunity and facilitates virus replication.
    Keywords:  EV71; PINK1; Parkin; extracellular mitochondria; mitophagy
    DOI:  https://doi.org/10.1096/fj.202403315R
  37. Autophagy Rep. 2025 ;4(1): 2503226
    Identification of a novel mechanism for regulation of the early autophagy machinery assembly by PKA.
    Miranda Bueno-Arribas, Olivier Vincent.
      The E3-like complex Atg12-Atg5-Atg16, which promotes Atg8 lipidation, is recruited to the autophagosomal membrane through the interaction of Atg16 with the PROPPIN/WIPI protein Atg21, as well as by the binding of Atg12 to Atg17, the scaffold protein of the Atg1 kinase complex in yeast. In order to gain insights into the molecular basis of Atg12-Atg17 interaction, we performed reverse two-hybrid screens to identify key-binding residues in both proteins and, based on these data, model the structure of this protein complex. Strikingly, we found that the Atg17 binding site in Atg12 overlaps with a PKA phosphorylation site and that PKA phosphorylation of Atg12 prevents Atg17 binding, revealing a new regulatory mechanism by which PKA regulates the assembly of the autophagy machinery.
    Keywords:  ATG12; ATG17; Autophagy; PKA; phosphoregulation; protein complex structure prediction; reverse two-hybrid
    DOI:  https://doi.org/10.1080/27694127.2025.2503226
  38. Autophagy Rep. 2024 ;3(1): 2403956
    Chaperone-mediated autophagy in fish: A key function amid a changing environment.
    Simon Schnebert, Emilio J Vélez, Maxime Goguet, Karine Dias, Vincent Véron, Isabel García-Pérez, Lisa M Radler, Emilie Cardona, Stéphanie Fontagné-Dicharry, Pierre Van Delft, Franziska Dittrich-Domergue, Amélie Bernard, Florian Beaumatin, Amaury Herpin, Beth Cleveland, Iban Seiliez.
      Chaperone-Mediated Autophagy (CMA) is a major pathway of lysosomal proteolysis critical for cellular homoeostasis and metabolism. While extensively studied in mammals, CMA's existence in fish has only been confirmed recently, offering exciting insights into its role in species facing environmental stress. Here, we shed light on the existence of 2 genes encoding the CMA-limiting factor Lamp2A (lysosomal associated membrane protein 2A) in rainbow trout (RT, Oncorhynchus mykiss), revealing distinct expression patterns across various tissues. Notably, RT lacking the most expressed Lamp2A exhibit profound hepatic proteome disturbances during acute nutritional stress, underscoring its pivotal role as a guardian of hepatic proteostasis. Building upon these findings, we introduce and validate the CMA activation score as a reliable indicator of CMA status, providing a valuable tool for detecting cellular stress in fish under environmental threats. Overall, our study offers new perspectives into understanding CMA from evolutionary and environmental contexts.
    Keywords:  CMA score; Chaperone-mediated autophagy; environment; fish; metabolism; rainbow trout; stress
    DOI:  https://doi.org/10.1080/27694127.2024.2403956
  39. Sci Rep. 2025 May 20. 15(1): 17488
    TMBIM1 promotes epithelial mesenchymal transition by accelerating autophagic degradation of E-cadherin in glioblastoma.
    Lun Gao, Junhui Liu, Yong Li, Ji'an Yang, Jiayang Cai, Long Wang, Zhang Ye, Shi'ao Tong, Gang Deng, Qianxue Chen, Qiang Cai.
      Glioblastoma (GBM; WHO grade IV) is well known for its highly aggressive and recurrent nature and accounts for approximately 50% of all gliomas. Dysregulation of epithelial-mesenchymal transition (EMT) can lead to malignant progression of GBM. Therefore, it is an urgent need to delineate the mechanisms by which molecular drivers affect EMT in GBM. We found for the first time that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) was overexpressed in GBM tissues compared with nontumor brain tissues and that its expression level was correlated with the degree of malignancy of glioma. Patients with high TMBIM1 expression had shorter overall survival times than those with low TMBIM1 expression. Importantly, TMBIM1 induced EMT and autophagy, and inhibition of autophagy reversed TMBIM1-induced EMT in both in vitro and in vivo assays. TMBIM1 induced EMT by downregulating E-cadherin expression, which mediated by in-habitation of autophagic degradation of E-cadherin. Inhibition of TMBIM1 expression dramatically decreased the levels of p-AMPKα Thr172 and p-ULK1 Ser317 in U87 and U251 cells and increased the level of p-mTOR Ser2448. In addition, inhibition of AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin)/ULK1 (unc-51-like autophagy-activating kinase 1) axis partially attenuated TMBIM1-induced autophagy. Our study provides a novel mechanism for the regulation of EMT in the process of GBM invasion and migration, indicating that suppression of TMBIM1 activity to attenuate autophagy may be a potential strategy for the treatment of GBM.
    Keywords:  AMPK-mTOR-ULK1 axis; Autophagy; Epithelial-mesenchymal transition; Glioblastoma; TMBIM1
    DOI:  https://doi.org/10.1038/s41598-025-01699-4
  40. Autophagy Rep. 2023 ;2(1): 2277582
    Structural biology of the Atg8 and Atg12 conjugation systems.
    Nobuo N Noda.
      Atg8 and Atg12 are ubiquitin-like proteins, conjugated to phosphatidylethanolamine (PE) and Atg5, respectively, through enzymatic reactions similar to ubiquitylation. The resultant Atg8-PE and Atg12-Atg5 conjugates play crucial roles in autophagy. Structural studies have been extensively performed on all Atg proteins (Atg3, Atg4, Atg5, Atg7, Atg8, Atg10, Atg12, Atg16) involved in these conjugation systems. This review summarizes structural studies and discusses mechanisms of conjugation and deconjugation reactions, as well as autophagic functions of the Atg8 and Atg12 conjugation systems.
    Keywords:  Atg10; Atg12; Atg16; Atg3; Atg4; Atg5; Atg7; Atg8; RavZ; structural biology
    DOI:  https://doi.org/10.1080/27694127.2023.2277582
  41. Autophagy Rep. 2023 ;2(1): 2215617
    Discovery of small-molecule inhibitors for the protein-protein interactions involving ATG5.
    Honggang Xiang, Renxiao Wang.
      The autophagy-related 12 (ATG12)-autophagy-related 5 (ATG5)-autophagy-related 16-like 1 (ATG16L1) ternary complex forms a dimer that facilitates the translocation of autophagy-related 8 (ATG8) proteins from autophagy-related 3 (ATG3) to phosphatidylethanolamine (PE). This event is fundamental for cargo sequestration and autophagy progression. Thus, one possible strategy for inhibiting autophagy is to disrupt the critical ATG5-ATG16L1 interaction during this process. So far very few known specific autophagy modulators can block autophagy effectively. We recently discovered a small-molecule compound, T1742, which is able to block the ATG5-ATG16L1 and ATG5-TECAIR interactions in vitro at the low-micromolar range (IC50 = 1~2 μM). Flow cytometry assay and western blot experiments indicated that T1742 can also effectively inhibit autophagy in living cells in a dose-dependent manner. To the best of our knowledge, T1742 represents the first small-molecule autophagy inhibitor that disrupts the protein-protein interactions involving ATG5. Such compounds may serve as a new chemical tool for deciphering the mechanism of autophagy or a potential candidate for therapeutic application.
    Keywords:  Autophagy inhibitor; autophagy-related 16-like 1; autophagy-related 5; binding assay; flow cytometry; structure-activity relationship; western blot
    DOI:  https://doi.org/10.1080/27694127.2023.2215617
  42. Autophagy Rep. 2024 ;3(1): 2291250
    TDP-43 Secretion via Extracellular Vesicles Is Regulated by Macroautophagy.
    Yoshinori Tanaka, Shun-Ichi Ito, Genjiro Suzuki.
      The pathological accumulation of the nuclear protein TDP-43 (TAR DNA-binding protein 43 kDa) in the cytoplasm is characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), and its spread through the brain and spinal cord is closely associated with the progression of these two diseases. However, the mechanisms through which the TDP-43 pathology propagates throughout the central nervous system remain unclear. We recently reported the role of (macro)autophagy in the secretion of TDP-43 via extracellular vesicles (EVs). We found that among the autophagy modulators, bafilomycin A1 (Baf) and GRN (granulin precursor) deficiency impair the formation of autolysosomes and promote the secretion of TDP-43 by EVs. TDP-43 loading on EVs involves autophagy-related proteins and the knockdown of TDP-43 augmented Baf-induced EV release. Thus, our results suggest that the loss-of-function of TDP-43 accelerates release of EVs possibly derived from autophagosomes, which may mediate cell-to-cell spread of the TDP-43 pathology.
    Keywords:  ALS; FTLD-TDP; TDP-43; autophagy; extracellular vesicle; lysosome; prion; progranulin
    DOI:  https://doi.org/10.1080/27694127.2023.2291250
  43. Autophagy Rep. 2024 ;3(1): 2409563
    Truncated tau disrupts autophagy and endolysosomal systems.
    Saskia J Pollack, Diane P Hanger, Wendy Noble, Maria Jimenez-Sanchez.
      
    Keywords:  Alzheimer’s disease; TFEB; Tau; autophagy; dementia; endosomes; lysosomes; tauopathies
    DOI:  https://doi.org/10.1080/27694127.2024.2409563
  44. Autophagy Rep. 2025 ;4(1): 2466120
    Role of neuronal fabp in autophagy and amyloid-β pathology in a Drosophila model of Alzheimer disease.
    Byoungyun Choi, Kyoung Sang Cho.
      FABP3 and FABP7 are members of the fatty acid-binding protein (FABP) family that transport fatty acids to intracellular organelles, which are elevated in patients with Alzheimer disease (AD). However, their role in the disease pathogenesis remain poorly understood. In a Drosophila model of AD, neuronal fabp knockdown inhibited autophagic flux and increased amyloid-beta (Aβ) aggregation, exacerbating neurodegeneration. Conversely, fabp overexpression had the opposite effect and improved memory. The modulation of Ecdysone-induced protein 75B (Eip75B) levels, the Drosophila homolog of peroxisome proliferator-activated receptor, a lipid-activated nuclear receptor that functions as a transcription factor, affected the expression of autophagy-related genes and the role of fabp in Aβ pathology. These results suggest that fabp regulates Aβ pathology through autophagy by modulating Eip75B and highlight the importance of proper fatty acid transport in neurons for autophagy regulation and Aβ pathogenesis.
    Keywords:  Amyloid beta; Drosophila; fatty acid-binding protein; pathogenesis; peroxisome proliferator-activated receptor
    DOI:  https://doi.org/10.1080/27694127.2025.2466120
  45. Eur J Med Chem. 2025 May 17. pii: S0223-5234(25)00539-2. [Epub ahead of print]294 117774
    Reversing an agonist into an inhibitor: Development of mTOR degraders.
    Liquan Zhu, Siyi Fu, Longfei Ma, Zhe Chen, Qian Zeng, Ruichen Li, Yiyu Zhou, Huijuan Qian, Xuli Meng, Jingyan Ge.
      Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for modulating protein function. In this study, we developed mTOR-targeting PROTACs by conjugating the mTOR agonist MHY-1485 to the Cereblon (CRBN) ligand pomalidomide, demonstrating that even activators can serve as effective warheads for targeted protein degradation. Through systematic screening, we identified PD-M6 as a potent bifunctional molecule capable of degrading mTOR (DC50 = 4.8 μM), reversing the proliferative effects of MHY-1485, and inhibiting cell proliferation (IC50 = 11.3 μM) while inducing autophagy, akin to the mTOR known inhibitor rapamycin. Proteomic analysis further revealed that PD-M6 downregulated key proteins in the mTOR signaling pathway, including LAMTOR1, MAPKAP1, and CASTOR1, which are involved in proteasome-mediated degradation, cell division, apoptosis, and lysosomal signaling. Notably, PD-M6 specifically induced the degradation of LAMTOR1. These findings highlight a novel approach for designing PROTACs from agonists, broadening the scope of targeted protein degradation strategies for therapeutic applications.
    Keywords:  Autophagy; Degradation; PROTACs; Proteomics; mTOR
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117774
  46. Autophagy Rep. 2024 ;3(1): 2432848
    Mechanistic insights into the interaction between optineurin with RAB8A.
    Jing Zhang, Lifeng Pan.
      OPTN (optineurin), an amyotrophic lateral sclerosis (ALS)-associated modifier, plays vital roles in autophagy and cellular vesicular transport in mammals. OPTN can associate with RAB8A and the GTPase-activating protein TBC1D17, and facilitate the negative regulation of RAB8A by TBC1D17 (TBC domain family member 17). Recently, we reported the biochemical and structural characterizations of the interactions between OPTN, RAB8A and TBC1D17. We determined the crystal structure of the leucine-zipper domain (LZD) of OPTN with the GTP-bound active RAB8A and uncovered the molecular mechanism underpinning the specific interaction of OPTN with RAB8A. Moreover, we revealed that OPTN LZD and the TBC (Tre-2/Bub2/Cdc16) domain of TBC1D17 competitively bind to active RAB8A, while the central coiled-coil domain of OPTN and the active RAB8A can simultaneously interact with TBC1D17 TBC. In summary, our study provided mechanistic insights into the interaction of OPTN with RAB8A, and revealed the interaction relationship among OPTN, RAB8A and TBC1D17.
    Keywords:  RAB8A; TBC1D17; Vesicular transport; optineurin
    DOI:  https://doi.org/10.1080/27694127.2024.2432848
  47. Autophagy Rep. 2023 ;2(1): 2256599
    Improved volume CLEM revealed that aberrant phagophores and RB1CC1/FIP200-containing clusters appear surround SQSTM1/p62 aggregates in Atg9a-deficient cells.
    Soichiro Kakuta, Junji Yamaguchi, Chigure Suzuki, Isei Tanida, Yasuo Uchiyama.
      ATG9A is an important membrane protein in mammalian macroautophagy. The formation of autophagosomes and phagophores is blocked in atg9a KO cells. However, it remains possible that residual membrane formation activity exists in these cells. These precursor structures that precede phagophores are, if they exist, rare and may be difficult to find. Here, we introduce the modified volume correlative light and electron microscopy (CLEM) method to analyze these structures three-dimensionally. In addition to target proteins, mitochondria were labeled as a landmark for precise correlation of slice images by a confocal fluorescence microscope and a focused ion beam scanning electron microscope. We found phagophores and small membrane vesicles near SQSTM1/p62 aggregates in atg9a KO cells, indicating that phagophores could be formed in atg9a-deficient cells, although they were immature and inefficient. Furthermore, we found that RB1CC1/FIP200-positive structures formed clusters around SQSTM1/p62 with ferritin and TAX1BP1. Taken together, our method contributes to the understanding of undiscovered fine structures. Abbreviations: CLEM: correlative light and electron microscopy; EM: electron microscopy; ER: endoplasmic reticulum; FIB-SEM: focused ion beam scanning electron microscopy; FM: fluorescence microscopy; GFP: green fluorescent protein; KO: knock out; MEF: mouse embryonic fibroblast; PBS: phosphate-buffered saline; ROI: region of interest; SEM: scanning electron microscopy.
    Keywords:  3D-CLEM; FIB-SEM; autophagosome; autophagy; electron microscopy; isolation membrane
    DOI:  https://doi.org/10.1080/27694127.2023.2256599
  48. Autophagy. 2025 May 19.
    ER tubular body: an ER-derived compartment for redirecting autophagy to secretory functions.
    Min Seok Song, Hun Ju Sim, Shin Hye Noh, Vivek Malhotra, Min Goo Lee.
      The secretion of proteins that do not follow the well-characterized endoplasmic reticulum (ER)-Golgi apparatus pathway, known as unconventional protein secretion (UCPS), is gradually revealing its complexities. Our study has identified an ER-based tubulovesicular network, termed ER tubular body (ER-TB), as a central compartment in this process. We demonstrate that ER-TBs are formed by two reticulophagy receptors, ATL3 and RTN3L, under conditions of cellular stress. In addition to their role in stress-induced secretion, the activation of UCPS via ER-TBs facilitates cell surface trafficking of trafficking-deficient transmembrane proteins such as ΔF508-CFTR. Furthermore, their involvement in ER remodeling and vesicle trafficking suggests a potential role in viral replication, particularly in the formation of membrane compartments utilized by positive-strand RNA viruses. By uncovering ER-TBs as key cellular structures in stress-induced UCPS and demonstrating their regulation by autophagy-related factors, our findings offer valuable insights into protein homeostasis, viral pathogenesis, and potential therapeutic strategies for diseases linked to trafficking defects.
    Keywords:  ATL3; ER stress; ER tubular body; RTN3L; compartment for unconventional protein secretion; unconventional protein secretion
    DOI:  https://doi.org/10.1080/15548627.2025.2508935
  49. Autophagy Rep. 2024 ;3(1): 2325265
    GRB2, a protein known for a long time with a new autophagy-regulating function.
    Silvia Vega-Rubin-de-Celis.
      BECN1 (BCL2 interacting myosin like coiled protein) is a major regulator of autophagy and a haploinsufficient tumor suppressor. BECN1 binds to multiple proteins and it is part of at least two different class III phosphatidylinositol (PI) 3 Kinase (PI3KC3) complexes that regulate autophagy and endocytic trafficking through the biosynthesis of phosphatidylinositol-3-phosphate. BECN1 and the activity of the PI3KC3 are regulated by post-translational modifications and/or subcellular localization. We recently discovered that GRB2 (growth factor receptor bound protein 2), an adaptor protein of several tyrosine kinases, interacts with BECN1 and regulates autophagy.1.
    Keywords:  BECN1; CAM assay; GRB2; PI3KC3; autophagy; tumorigenesis
    DOI:  https://doi.org/10.1080/27694127.2024.2325265
  50. Cell Death Dis. 2025 May 19. 16(1): 402
    Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos.
    Beatriz Villarejo-Zori, Juan Zapata-Muñoz, Elena Sierra-Filardi, Ignacio Ramírez-Pardo, Lambert Montava-Garriga, Ian G Ganley, Patricia Boya.
      Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. Olaparib and DFP rescue parthanatos induced cell death after MNU-induced retinal degeneration. High doses of MNU induce lysosomal damage and mitophagy inhibition. In addition, MNU produces DNA damage and increases oxidative stress, resulting in PAR polymer formation and retinal degeneration (orange panel). DFP and Olaparib are able to rescue retinal degeneration downstream of lysosomal damage (green panel). Sub-lethal doses of MNU induce a peak in mitophagy that is BNIP3L-BNIP3 dependent (blue panel).
    DOI:  https://doi.org/10.1038/s41419-025-07686-x
  51. Front Cell Dev Biol. 2025 ;13 1538377
    Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.
    Raffaella Bonavita, Fulvia Vitale, Luigi Vittorio Verdicchio, Sarah V Williams, Maria Gabriella Caporaso, Angeleen Fleming, Maurizio Renna.
      Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's and Huntington's diseases as well as ataxias and fronto-temporal disorders are all characterized by the progressive accumulation of protein aggregates (amyloids) into inclusions bodies. In addition, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of some of these disease-relevant proteins to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the role of small heat shock proteins (sHSPs) and autophagy in cellular quality control and turn-over of the major aggregation-prone proteins associated to neurodegenerative disorders. We also highlight the advanced research progress on mechanisms regulating unconventional secretion, secretory autophagy and EVs biogenesis and their contribution in the pathological processes underlining these diseases. Finally, we outline the latest research on the roles of EVs in neurodegenerative diseases and their potential diagnostic and therapeutic significance for the treatment of these clinically relevant conditions.
    Keywords:  autophagy; extracellular vesicles and exosomes; neurodegenerative diseases; protein misfolding; protein oligomerization and aggregation; small heat shock proteins; unconventional protein secretion
    DOI:  https://doi.org/10.3389/fcell.2025.1538377
  52. Autophagy Rep. 2025 ;4(1): 2486445
    The role of autophagy in ischemic brain injury.
    Emily Osterli, Yujung Park, Kurt Hu, Gary Kasof, Thorsten Wiederhold, Chunli Liu, Bingren Hu.
      Ischemic brain injury occurs in many clinical settings, including stroke, cardiac arrest, hypovolemic shock, cardiac surgery, cerebral edema, and cerebral vasospasm. Decades of work have revealed many important mechanisms related to ischemic brain injury. However, there remain significant gaps in the scientific knowledge to reconcile many ischemic brain injury events. Brain ischemia leads to protein misfolding and aggregation, and damages almost all types of subcellular organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, etc. Irreparably damaged organelles and insoluble protein aggregates are normally removed by autophagy. The build-up of common autophagic components, such as LC3, p62, and ubiquitinated proteins, are generally observed in brain tissue samples in animal models of both global and focal brain ischemia, but the interpretation of the role of these autophagy-related changes in ischemic brain injury in the literature has been controversial. Many pathological events or mechanisms underlying dysfunctional autophagy after brain ischemia remain unknown. This review aims to provide an update of the current knowledge and future research directions regarding the critical role of dysfunctional autophagy in ischemic brain injury.
    Keywords:  Amphisomes; N-ethylmaleimide sensitive factor protein; autophagosome; autophagy related; cathepsins; late endosome; lysosomes; microtubule-associated protein 1A/1B–light chain 3; sequestosome 1; soluble NSF attachment proteins receptor
    DOI:  https://doi.org/10.1080/27694127.2025.2486445
  53. Exp Eye Res. 2025 May 19. pii: S0014-4835(25)00208-8. [Epub ahead of print] 110437
    PINK1-mediated mitochondrial autophagy protects lens epithelial cells by reducing ROS and apoptosis.
    Xiangyu Liu, Meiyu Wang, Zhenzhen Ji, Xuanlin Zhu, Jinchang Tian, Yingxin Chen, Jun Cai, Mei Dong, Zhijian Li.
      Cataracts are one of the primary causes of blindness worldwide; however, their pathogenesis remains unclear. Oxidative stress and apoptosis are two dominant inducers in the progression of cataracts; however, little is known about the specific mechanisms associated with mitophagy. This study aimed to investigate the role of PTEN-induced putative kinase 1(PINK1)-mediated mitophagy in cataract development. Initially, we induced a rat cataract model using sodium selenite and observed the upregulated expression of PINK1 and other autophagy-related proteins within lens epithelial cells, accompanied by apoptosis. Furthermore, the survival rate of human lens epithelial cells was significantly reduced by H2O2 treatment. However, PINK1 overexpression reduced ROS levels, allowing cells to survive. This reduction in reactive oxygen species (ROS) levels led to a decrease in cleaved caspase-3 and Bcl-2-associated X protein (Bax) expression and an increase in B-cell lymphoma 2 (Bcl-2) levels. In summary, PINK1 maintains mitochondrial functional stability and inhibits apoptosis by activating mitophagy, thus potentially playing a crucial protective role in cataract pathogenesis.
    Keywords:  Apoptosis; Cataract; Mitophagy; PINK1; ROS
    DOI:  https://doi.org/10.1016/j.exer.2025.110437
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