bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–02–15
twenty-six papers selected by
Viktor Korolchuk, Newcastle University
  1. Autophagy in kidney physiology: from cellular quality control to organ metabolism.
  2. Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.
  3. Rapid optogenetic manipulation of autophagy reveals that the nuclear pore complex is a robust autophagy substrate.
  4. Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
  5. p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
  6. Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.
  7. Expression of IMD-CBM peptide induces the autophagic degradation of CAV1 (caveolin 1) to inhibit LDL transcytosis and retard diabetic atherosclerosis.
  8. ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation.
  9. Mammalian lipophagy: process and function.
  10. Tracking Focal Adhesion Turnover: A Novel Reporter for FA-Phagy Flux.
  11. The DNA Methylation-Autophagy Axis: A Driver of MSC Fate Imbalance in Skeletal Aging and Osteoporosis.
  12. AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
  13. Negative feedback regulation of STING signaling by TAX1BP1-directed Golgiphagy.
  14. Structure and function of the yeast amino acid-sensing SEAC-EGOC supercomplex.
  15. The Autophagy Receptor NDP52 Recruits the E3 Ligase ASB2 to Mediate NOX4 Degradation, Suppressing Cardiomyocyte Ferroptosis and Ameliorating Heart Failure.
  16. From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.
  17. Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models.
  18. TDP-43 Mediates Autophagic Degradation of Yki by Stabilizing Ref(2)P in Drosophila.
  19. A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.
  20. Isoflurane aggravates pre-existing proteotoxicity in adult nematodes by suppressing mitochondrial fitness.
  21. Histochemical perspectives on VDAC1-associated autophagy signaling in Alzheimer's disease brain.
  22. Adipose Tissue-Derived Exosome and miR-142a-3p Alleviate Acute Lung Injury by Inhibiting HMGB1-Driven Autophagy.
  23. Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis.
  24. Nucleophagy: The guardian of genome stability - from molecular mechanisms to disease associations.
  25. ULK1 activates NCOA4‑mediated ferritinophagy via the Beclin1/VPS34 complex in cardiomyocyte hypertrophy.
  26. Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism.
  1. Autophagy Rep. 2026 ;5(1): 2622228
    Autophagy in kidney physiology: from cellular quality control to organ metabolism.
    Takeshi Yamamoto, Satoshi Minami, Yoshitaka Isaka.
      Autophagy is a cellular process that maintains kidney physiology by recycling intracellular components to preserve homeostasis. In the kidney, autophagy supports energy metabolism and integrity across multiple cell types. Its regulation is tightly governed by nutrient availability, hormonal cues, and oxygen levels, primarily through signaling pathways such as mechanistic target of rapamycin kinase (mTOR), AMP-activated protein kinase (AMPK), and transcription factor EB (TFEB). Under physiological conditions, autophagy is dynamically regulated to meet metabolic demands. However, aging, obesity, and metabolic stress impair lysosomal function, leading to a pathological state termed autophagic stagnation, in which autophagosomes accumulate but degradative flux is compromised. Rather than being uniformly protective, this stagnation promotes cellular damage and contributes to kidney disease progression. Notably, autophagic stagnation in proximal tubular epithelial cells (PTECs) contributes to acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition and exacerbates lipotoxicity in obesity-related kidney disease. Recent studies highlight the importance of transcriptional regulators - including TFEB and MondoA - in maintaining autophagic activity and mitochondrial homeostasis. Therapeutic strategies aimed at restoring autophagic flux - pharmacologically or through lifestyle interventions such as caloric restriction - hold promise for preserving kidney function. Deeper understanding of cell type - specific autophagy regulation will be critical for developing targeted and context-specific therapies.
    Keywords:  Mitophagy; Rubicon; autophagic stagnation; fibroblast growth factor 21 (FGF21); lipophagy; lysophagy; proximal tubular epithelial cells (PTECs)
    DOI:  https://doi.org/10.1080/27694127.2026.2622228
  2. Arch Toxicol. 2026 Feb 07.
    Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.
    Shunichi Hatamiya, Masatsugu Miyara, Nanako Takahashi, Ami Oguro, Yaichiro Kotake.
      Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single membranes (CASM) is a noncanonical LC3‑lipidation pathway activated by various stressors, distinct from canonical autophagy. We previously showed that TBT reduces lysosomal acidity and inhibits autophagy in SH-SY5Y cells. Furthermore, we observed TBT-induced LC3-II accumulation, which was reduced by bafilomycin A1, and tubular LC3-positive structures as hallmarks of CASM. In this study, we investigated whether TBT activates CASM. TBT (700 nM) induced LC3-II accumulation, which was completely blocked by bafilomycin A1 in SH-SY5Y and HeLa cells. Unlike autophagy, TBT induced LC3-II accumulation even under class III PI3K inhibition by wortmannin and in FIP200-knockout cells. Salmonella effector protein SopF, which inhibits V-ATPase-ATG16L1 association required for CASM, inhibited TBT-induced LC3-II accumulation. In FIP200-knockout cells, TBT induced LC3 accumulation on lysosomes, the primary CASM target. TBT also promoted nuclear translocation of transcription factor EB (TFEB) in a SopF-sensitive manner. Together, these results identify CASM as a lysosomal stress response to TBT, induced via the V-ATPase-ATG16L1 axis, leading to TFEB activation. This mechanism provides a toxicological framework for understanding xenobiotic-induced lysosomal adaptations.
    Keywords:  CASM; LC3; Lysosome; Noncanonical autophagy; TFEB; Tributyltin
    DOI:  https://doi.org/10.1007/s00204-026-04300-7
  3. bioRxiv. 2026 Feb 03. pii: 2026.02.03.703609. [Epub ahead of print]
    Rapid optogenetic manipulation of autophagy reveals that the nuclear pore complex is a robust autophagy substrate.
    Payel Mondal, Amanda Cyril, Louis Parham, Dana Mamriev, Igor Wierzbicki, Celina Shen, David J Gonzalez, Maximiliano A D'Angelo, Christina G Towers.
      Autophagy, a conserved recycling process, manages intracellular quality control to mitigate stress. To determine the rapid effects of autophagy perturbation, we developed the first optogenetic tool to rapidly inhibit autophagy, termed ASAP. Our approach selectively inhibits autophagy within 5 minutes, providing a precise and dynamic approach to study autophagy regulation. Proteomic profiling with ASAP revealed the most tightly regulated autophagy substrates along with novel, previously unidentified substrates, including nuclear pore complex (NPC) proteins. Interestingly, autophagy regulates quality control of incomplete NPCs still in the cytoplasm via specific LC3-interacting regions (LIRs), sparing NPCs embedded in the nuclear envelope. Upon rapid autophagy inhibition, incomplete NPCs accumulate and instead of undergoing autophagic degradation, cytoplasmic NPCs aggregate in processing bodies. Using ASAP, we demonstrate rapid and specific inhibition of autophagy, revealing that the nuclear pore complex is a tightly regulated autophagy substrate.
    DOI:  https://doi.org/10.64898/2026.02.03.703609
  4. Autophagy. 2026 Feb 12. 1-3
    Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
    Hanna Hakansson, Jack H Howden, Josef T Kittler.
      Mitochondria regulate ATP production, calcium buffering, and apoptotic signaling, and clearing dysfunctional mitochondria by mitophagy is essential for cellular homeostasis. While PINK1-dependent mitophagy is well-characterized in neurons, its function in glial cells such as astrocytes is less understood. Our study demonstrates that PINK1-mitophagy in astrocytes occurs faster and with less spatial restriction compared to neurons. This pathway was specifically regulated in astrocytes by the glycolytic enzyme, HK2 (hexokinase 2), which forms a glucose-dependent complex with PINK1 following mitochondrial damage. Inflammation also induces HK2-PINK1 mitophagy, and its activation in astrocytes protects against cytokine-induced neuronal death. Our findings characterize a novel HK2-PINK1 pathway in astrocytes that bridges mitophagy, metabolism, and immune signaling.Abbreviation: HK2: hexokinase 2; PD: Parkinson disease; PINK1: PTEN induced kinase 1; S65: serine 65.
    Keywords:  Astrocyte; HK1; PINK1; mitochondria; mitophagy; neurodegeneration; parkin
    DOI:  https://doi.org/10.1080/15548627.2026.2623987
  5. Aging Cell. 2026 Feb;25(2): e70402
    p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
    Shan Sun, Jiaqi Xin, Yingping Zhang, Bojun Yang, Dan Su, Rui Ni, Qilian Ma, Ningning Li, Guoqiang Ma, Qiang Peng, Siqian Chen, Jochen H M Prehn, Kin Yip Tam, Hongfeng Wang, Zheng Ying.
      Mitochondrial quality control is tightly associated with aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD-associated protein p62 drives "mitochondrial clustering" (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin-mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form "grape-like" clusters during PINK1/Parkin-mediated mitophagy, which is tightly associated with aging-related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a "brake" to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD-related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the "brake" machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.
    DOI:  https://doi.org/10.1111/acel.70402
  6. Autophagy. 2026 Feb 10. 1-2
    Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.
    Qiwang Xiang, Yang Liu, Jiou Wang.
      Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The ensuing lysosomal dysfunction leads to autophagosome accumulation and defective clearance of accumulated cytoplasmic toxic proteins like TARDBP/TDP-43. Genetic and pharmacological inhibition of ITCH restores autolysosomal degradation and protects neurons in both mammalian and Drosophila models. Aberrant buildup of the deubiquitinase USP11 drives ITCH accumulation, intensifying neuronal proteotoxic stress in individuals with AD and ALS. These findings reveal a mechanistic pathway connecting Golgi disorganization, autolysosomal impairment, and proteotoxic stress in neurodegeneration.
    Keywords:  Autophagy; Golgi fragmentation; ITCH; USP11; lysosome; neurodegenerative diseases
    DOI:  https://doi.org/10.1080/15548627.2026.2629295
  7. Autophagy. 2026 Feb 13.
    Expression of IMD-CBM peptide induces the autophagic degradation of CAV1 (caveolin 1) to inhibit LDL transcytosis and retard diabetic atherosclerosis.
    Li Wang, Xiong Jia, Xiangli Bai, Ying Zhao, Wenzhuo Cheng, Meng Shu, Yan Shu, Liyin Zhang, Ruonan Wang, Si Jin.
      Atherosclerosis is attributable to a series of diabetes-related complications. CAV1 (caveolin 1)-mediated low-density lipoprotein (LDL) particle transcytosis across endothelial cells (ECs) is the initial step of atherosclerosis. MAP1LC3/LC3-interacting regions in the intramembrane domain (IMD) of CAV1 were buried in the caveolae and were not accessible for LC3B interaction, protecting CAV1 from autophagic degradation. However, the CSD domain of CAV1, exposed in the cytosol, directly interacted with a CBM domain of LC3B and inhibited autophagy. Therefore, the peptide IMD-CBM was constructed to induce the selective autophagic degradation of CAV1 and suppress LDL transcytosis in diabetic atherosclerosis. EC-specific expression of IMD-CBM was achieved using adenovirus. IMD-CBM directly interacted with CAV1 and LC3B in ECs, leading to the selective autophagic degradation of CAV1, activation of autophagy, and subsequent inhibition of LDL transcytosis. IMD-CBM promoted the autophagic degradation of CAV1 and consequently reduced the area of atherosclerotic plaques in apoe-/- diabetic atherosclerotic mice. Overall, IMD-CBM expedited the autophagic degradation of CAV1 and inhibited high glucose-induced LDL transcytosis, highlighting its potential as a novel translatable strategy for the management of diabetic atherosclerosis.
    Keywords:  Atherosclerosis; CAV1-binding motif/CBM; CAV1/caveolin 1; LDL transcytosis; autophagy; intramembrane domain/IMD
    DOI:  https://doi.org/10.1080/15548627.2026.2631946
  8. Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2523367123
    ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation.
    Navroop K Dhaliwal, Octavia Yifang Weng, Ai Tian, Aditi Aggarwal, Mai Ahmed, Guoria Sun, Afrin Bhattacharya, Wendy W Y Choi, Haruka Nishimura, Pragnya Chakraborty, Xiaoxue Dong, Yuncheng Wu, Michael D Wilson, Lu-Yang Wang, Luis F Parada, Julien Muffat, Yun Li.
      Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors (NPs) and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including NP hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.
    Keywords:  PTEN; actin; human pluripotent stem cells; mTOR signaling; neurodevelopmental disorders
    DOI:  https://doi.org/10.1073/pnas.2523367123
  9. Autophagy. 2026 Feb 12.
    Mammalian lipophagy: process and function.
    Rui Zhao, Enyong Dai, Rui Kang, Jiao Liu, Daniel J Klionsky, Daolin Tang, Yangchun Qu, Yuanqiang Lin, Xinyue Zhang.
      Lipophagy, the selective autophagic degradation of lipid droplets (LDs), is a key mechanism for lipid homeostasis and cellular adaptation to metabolic and stress conditions. In mammals, lipophagy is governed by signaling pathways, LD-associated receptors (e.g. SQSTM1/p62, NBR1, OPTN, SPART, OSBPL8, DDHD2, VPS4A, ATG14, and TP53INP2), and transcription factors (TFEB, TFE3, FOXO1, PPARA, PPARG, and SREBF1/SREBP1) that coordinate LD recognition, sequestration, and lysosomal degradation. Dysregulated lipophagy contributes to the pathogenesis of metabolic and age-related diseases, including metabolic dysfunction-associated steatotic liver disease/nonalcoholic fatty liver disease (MASLD/NAFLD), alcoholic liver disease, diabetes, atherosclerosis, neurodegeneration and cancer. Several recent reviews have discussed lipophagy from different angles, including its roles in metabolic disorders, central nervous system diseases, and fundamental mechanisms across species. In contrast, this review focuses specifically on mammalian lipophagy by synthesizing the latest mechanistic insights into receptor-mediated recognition, transcriptional regulation, and signaling integration. We also outline unresolved questions and conceptual gaps - such as how lipophagy is selectively activated, how it coordinates with lipolysis, and whether distinct receptor codes exist in tissue- and disease-specific contexts - that remain unanswered in the current literature.
    Keywords:  Autophagy receptor; disease; lipid droplets; lipophagy; transcription factor
    DOI:  https://doi.org/10.1080/15548627.2026.2632256
  10. Cells. 2026 Feb 06. pii: 306. [Epub ahead of print]15(3):
    Tracking Focal Adhesion Turnover: A Novel Reporter for FA-Phagy Flux.
    Kuizhi Qu, Mengjun Dai, Ying Jiang, Sophie Liu, John P Hagan, Louise D McCullough, Zhen Xu, Yan-Ning Rui.
      Focal adhesions (FAs) are critical multi-protein complexes regulating cell adhesion, migration, and survival, and their dysregulation contributes to cancer metastasis and vascular diseases. Despite extensive research on FA formation, little is known about FA turnover, particularly its regulation by autophagy. This study introduces a novel tandem fluorescence reporter capable of tracking the entire FA-phagy flux, from autophagosome formation to lysosomal degradation. The reporter, based on a red-green fluorescence system with a lysosome-specific cleavage site, integrates seamlessly into endogenous focal adhesion complexes, demonstrating sensitivity and specificity to autophagy stimuli. Validated in multiple cell lines, the tool revealed dynamic FA-phagy responses to starvation-induced autophagy and the involvement of autophagy regulators such as mTOR and ATG genes. This versatile reporter provides a powerful tool for investigating FA-phagy mechanisms, with significant implications for cancer biology and vascular research.
    Keywords:  FA-phagy; autophagy; focal adhesions; lysosome; new assay
    DOI:  https://doi.org/10.3390/cells15030306
  11. Biology (Basel). 2026 Jan 24. pii: 218. [Epub ahead of print]15(3):
    The DNA Methylation-Autophagy Axis: A Driver of MSC Fate Imbalance in Skeletal Aging and Osteoporosis.
    Gaojie Song, Xingnuan Li, Jianjun Xiong, Lingling Cheng.
      Age-related osteoporosis is driven in part by senescence-associated rewiring of bone marrow mesenchymal stem cells (MSCs) from osteogenic toward adipogenic fates. Accumulating evidence indicates that epigenetic drift and reduced autophagy are not isolated lesions but are mechanistically coupled through a bidirectional DNA methylation and autophagy axis. Here, we summarize how promoter hypermethylation of genes involved in autophagy and osteogenesis suppresses autophagic flux and osteoblast lineage transcriptional programs. Conversely, autophagy insufficiency reshapes the methylome by limiting methyl donor availability, most notably S-adenosylmethionine (SAM), and by reducing the turnover of key epigenetic regulators, including DNA methyltransferases (DNMTs), ten-eleven translocation (TET) dioxygenases, and histone deacetylases (HDACs). This self-reinforcing circuitry exacerbates mitochondrial dysfunction, oxidative stress, and inflammation driven by the senescence-associated secretory phenotype (SASP), thereby stabilizing adipogenic bias and progressively impairing marrow niche homeostasis and bone remodeling. We further discuss therapeutic strategies to restore balance within this axis, including selective modulation of epigenetic enzymes; activation of AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) signaling with downstream engagement of Unc-51-like autophagy-activating kinase 1 (ULK1) and transcription factor EB (TFEB); targeting sirtuin pathways; mitochondria- and autophagy-supportive natural compounds; and bone-targeted delivery approaches or rational combination regimens.
    Keywords:  DNA methylation; MSCs; aging; autophagy; osteoporosis
    DOI:  https://doi.org/10.3390/biology15030218
  12. Autophagy. 2026 Feb 09.
    AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
    Florentina Negoita, Conchita Fraguas Bringas, Kristina Hellberg, Katarzyna M Luda, Hongling Liu, Zhiyuan Li, Joyceline Cuenco, Jin-Feng Zhao, Gajanan Sathe, Ian G Ganley, Gopal P Sapkota, Kei Sakamoto.
      TFEB (transcription factor EB) is a critical regulator of lysosomal biogenesis, macroautophagy/autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were reported to be essential for transcriptional activation of TFEB. In sharp contrast to this proposition, we demonstrate that AMPK activation leads to the dephosphorylation of the C-terminal sites. We show that a synthetic peptide encompassing the C-terminal serine residues of TFEB is a poor substrate of AMPK in vitro. Treatment of cells with an AMPK activator (MK-8722), glucose deprivation or MTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at the MTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722- but not torin1-induced dephosphorylation and induction of the TFEB target genes.
    Keywords:  BAY-3827; MK-8722; MTOR; TFE3; coordinated lysosomal expression and regulation; reversible phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2026.2629720
  13. Nat Commun. 2026 Feb 11.
    Negative feedback regulation of STING signaling by TAX1BP1-directed Golgiphagy.
    Sujit Suklabaidya, Suchitra Mohanty, Irene E Reider, Jesse White, Dominic Colter, Sarah M McCormick, Noula Shembade, Young Bong Choi, Christopher C Norbury, Edward W Harhaj.
      The cGAS-STING pathway is a critical regulator of type I Interferon (IFN) and inflammation upon cytosolic DNA-sensing. cGAS-STING signaling termination is regulated by lysosomal-mediated degradation of STING; however, the mechanisms controlling the inhibitory targeting of STING are incompletely understood. Here, we identify the selective autophagy receptor TAX1BP1 as a negative regulator of the cGAS-STING pathway. TAX1BP1-deficient macrophages activated by cGAS or STING agonists accumulate higher-order STING aggregates, exhibit heightened STING signaling, and increased production of type I IFN and proinflammatory cytokines. Mechanistically, TAX1BP1 promotes STING degradation through microautophagy by facilitating the interaction of STING with the ESCRT-0 protein HGS. Furthermore, STING activation is associated with the swelling and fragmentation of the Golgi apparatus, and TAX1BP1 and p62/SQSTM1 are essential for the autophagic degradation of fragmented Golgi (Golgiphagy). Our findings suggest that STING activation at the Golgi is coupled to its downregulation by Golgiphagy to restrict innate immune responses.
    DOI:  https://doi.org/10.1038/s41467-026-69422-z
  14. Nat Struct Mol Biol. 2026 Feb 12.
    Structure and function of the yeast amino acid-sensing SEAC-EGOC supercomplex.
    Lucas Tafur, Lenny Bonadei, Yiqiang Zheng, Caroline Gabus, Robbie Loewith.
      The Seh1-associated complex (SEAC; GATOR in mammals) transduces amino acid signals to the Target of Rapamycin Complex 1 (TORC1), a master regulator of cell growth. The SEAC is composed of two subcomplexes, SEACIT (GATOR1), an inhibitor of TORC1 that has GAP activity against Gtr1, and SEACAT (GATOR2), which appears to regulate SEACIT. However, the molecular details of this regulation are unclear. Here we determined the cryo-electron microscopy structure of the SEAC bound to its substrate, the EGOC (Ragulator-Rag), and studied its function in TORC1 amino acid signaling. A single SEAC can interact with two EGOC molecules via SEACIT, binding exclusively to the 'active' version of the EGOC, without involvement of SEACAT. The GAP activity of the SEACIT is essential for the regulation of TORC1 by amino acids and its loss phenocopies the lack of Gtr1-Gtr2, establishing the SEAC-EGOC complex as an amino acid-sensing hub. Compared to other SEACAT subunits, the loss of Sea2, or its N-terminal β-propeller domain, yielded strong defects in amino acid signaling to TORC1. Our results suggest that the Sea2 β-propeller recruits a GAP inhibitor to mediate fast amino acid signaling to TORC1, with additional pathways acting with slower kinetics.
    DOI:  https://doi.org/10.1038/s41594-026-01746-2
  15. Free Radic Biol Med. 2026 Feb 07. pii: S0891-5849(26)00111-5. [Epub ahead of print]
    The Autophagy Receptor NDP52 Recruits the E3 Ligase ASB2 to Mediate NOX4 Degradation, Suppressing Cardiomyocyte Ferroptosis and Ameliorating Heart Failure.
    Shouguo Yang, Jian Wu, Xiaoyue Song, Hong Jiang, Yunzeng Zou, Lei Zhang, Junbo Ge.
       BACKGROUND: Heart failure (HF) is characterized by cardiomyocyte loss. While ferroptosis driven by NOX4 contributes to HF, how autophagy regulates NOX4 stability remains unclear.
    METHODS: Using in vitro (isoproterenol-induced) and in vivo (TAC-induced) HF models, we combined pharmacological and genetic approaches with co-IP and molecular docking to investigate the autophagy-NOX4 axis.
    RESULTS: We identified a novel pathway wherein autophagy activation prompts the receptor NDP52 to bind NOX4 and recruit the E3 ligase ASB2, mediating K48-linked ubiquitination and autophagic degradation of NOX4. This process suppressed ferroptosis and ameliorated cardiomyocyte injury. The NOX4 inhibitor GLX351322, alone or combined with the autophagy activator metformin, conferred significant cardioprotection in vivo.
    CONCLUSION: Our findings reveal the 'autophagy-NDP52-ASB2-NOX4' axis as a crucial mechanism coupling autophagy to ferroptosis in HF, highlighting its therapeutic potential.
    Keywords:  Autophagy; Ferroptosis; Heart failure; NADPH Oxidase 4 (NOX4); NDP52/ASB2 Axis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.014
  16. Int J Mol Sci. 2026 Jan 23. pii: 1136. [Epub ahead of print]27(3):
    From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.
    Angelo Jamerlan, John Hulme.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation).
    Keywords:  TDP-43 proteinopathy; amyotrophic lateral sclerosis (ALS); autophagy-lysosome pathway (ALP); frontotemporal dementia (FTD); neurodegeneration; phase separation; post-translational modifications (PTMs); proteostasis collapse; ubiquitin-proteasome system (UPS)
    DOI:  https://doi.org/10.3390/ijms27031136
  17. bioRxiv. 2026 Jan 29. pii: 2026.01.28.702341. [Epub ahead of print]
    Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models.
    Nancy León-Rivera, Brayden Chin, Ashley Quintana, Sofia Bustamante-Eguíguren, Anthony Gacasan, Monica Nanni, Jayanta Debnath, Teresa Monkkonen.
      Autophagy, a key lysosomal degradation pathway regulating metabolic adaptation in cancer, plays fundamental roles in both the tumor and host stromal compartments during cancer progression. An important unanswered question is whether and how autophagy in specific host stromal elements, such as endothelial cells, influences metastasis. Here, we scrutinize how the genetic loss of autophagy in endothelial cells impacts primary tumor progression and metastasis in the Polyoma Middle T ( PyMT ) model of luminal B breast cancer. In both autochthonous and orthotopic mammary transplant models, PyMT primary tumor growth is significantly delayed upon endothelial cell Atg12 or Atg5 genetic deletion ( Atg12 or 5 ECKO), which correlates with increased tumor cell apoptosis and HIF1α activation. In contrast, PyMT -bearing Atg12 ECKO mice exhibit increased metastasis, as well as higher rates of primary tumor and lung metastatic recurrence following surgical resection of PyMT primary tumors. Experimental metastasis assays further corroborate that loss of endothelial cell autophagy in Atg12 ECKO host animals promotes PyMT metastatic colonization and outgrowth, resulting in increased lung metastases compared to controls. Similarly, in the Rat Insulin Promoter T antigen pancreatic neuroendocrine tumor (RT2-PNET) model, endothelial cell deletion of Atg12 promotes liver micro-metastases. Taken together, these results from distinct preclinical cancer models reveal that endothelial cell autophagy suppresses metastatic seeding and progression and broach that autophagy inhibition in host endothelial cells may adversely influence the efficacy of systemic autophagy-lysosomal pathway inhibition in the clinical oncology setting.
    DOI:  https://doi.org/10.64898/2026.01.28.702341
  18. FASEB J. 2026 Feb 28. 40(4): e71572
    TDP-43 Mediates Autophagic Degradation of Yki by Stabilizing Ref(2)P in Drosophila.
    Dongyue Liu, Yufang Xu, Haochuan Wang, Shuai Huang, Shuangxi Li.
      The transcriptional co-activator Yki, the central effector of the Hippo signaling pathway, plays essential roles in regulating tissue growth, regeneration, and tumorigenesis. Although upstream signaling mechanisms controlling Yki activity have been extensively characterized, the molecular mechanisms that govern Yki protein homeostasis remain incompletely understood. In this study, we identify TAR DNA-binding protein 43 (TDP-43) as a critical regulator of Yki proteostasis and demonstrate that stabilization of the autophagic receptor Ref(2)P is indispensable for TDP-43-mediated Yki turnover. Our findings reveal that TDP-43 elevates Ref(2)P levels through two distinct mechanisms. At the post-translational level in the cytoplasm, TDP-43 disrupts the interaction between Ref(2)P and the kinase Dco, thereby preventing phosphorylation-dependent proteasomal degradation of Ref(2)P. At the post-transcriptional level in the nucleus, TDP-43 promotes Ref(2)P mRNA stability by interacting with the nuclear m6A reader protein Ythdc1, which facilitates recognition of N6-methyladenosine (m6A)-modified Ref(2)P transcripts and protects them from decay. Together, these findings delineate a dual regulatory mechanism by which TDP-43 controls Ref(2)P abundance and Yki proteostasis, providing new insights into the fine-tuning of Hippo pathway activity.
    Keywords:   Drosophila melanogaster ; Ref(2)P; TDP‐43; Yki
    DOI:  https://doi.org/10.1096/fj.202503852RR
  19. bioRxiv. 2026 Jan 29. pii: 2026.01.28.702105. [Epub ahead of print]
    A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.
    Qiang Xiao, Zi Gao, Seth Allen, Danny Garza, Richard I Morimoto, Jeffery W Kelly.
      Tau accumulation is a central driver of neurodegenerative diseases, yet strategies to promote its clearance remain limited. We developed a HaloTag-4R-Tau sensor in human iPSC-derived neurons (iNeurons) that enables sensitive monitoring the kinetics of both lysosomal partitioning and overall cellular turnover of tau. Using this sensor, we screened a small collection of small-molecule modulators of proteostasis network function and identified Neddylation inhibition by Pevonedistat as a robust promoter of soluble tau degradation. Mechanistic analysis including proteomic profiling revealed that Neddylation inhibition hastens HaloTag-Tau clearance via compensatory activation of a proteasome-dependent pathway(s) as well as the autophagy-lysosome pathway. Our findings establish a powerful tool for probing tau homeostasis and highlight Neddylation inhibition as a potential therapeutic approach for enhancing both proteasome and lysosome-mediated tau clearance in tauopathies.
    DOI:  https://doi.org/10.64898/2026.01.28.702105
  20. Sci Rep. 2026 Feb 10.
    Isoflurane aggravates pre-existing proteotoxicity in adult nematodes by suppressing mitochondrial fitness.
    Tayir Elami, Huadong Zhu, Reut Bruck-Haimson, Vijigisha Srivastava, Adam Zaretsky, Irit Cohen, Einav Gross, Ehud Cohen.
      Post operative delirium (POD) is an acute complication, characterized by fluctuating attention and confusion, which may develop and persist into cognitive decline. POD is most commonly observed in elderly patients, particularly those with preexisting cognitive impairments. Isoflurane, a widely used volatile anesthetic, is associated with POD. However. how exposure to isoflurane affects the integrity of the proteome is largely obscure. Utilizing the nematode C. elegans, we found that isoflurane leads to a long-lasting decline in protein homeostasis (proteostasis) of adult animals that express neurodegeneration-causing, abnormally long poly-glutamine stretches. Isoflurane-induced proteostasis impairments are dependent on the aging-regulating transcription factors DAF-16/FOXO and SKN-1/NRF, and can be alleviated by the knockdown of certain components of the mitophagy mechanism. Accordingly, induction of mitochondrial biogenesis protects worms that are challenged by protein aggregation from isoflurane-induced proteotoxicity. Our observations provide novel insights into the mechanism that links isoflurane, proteotoxicity and POD, and highlight the potential of mitophagy modulators as alleviators of POD.
    Keywords:   C. elegans ; Aging; Isoflurane; Mitochondria; Proteostasis; Volatile anesthetics
    DOI:  https://doi.org/10.1038/s41598-026-38591-8
  21. Acta Histochem. 2026 Feb 10. pii: S0065-1281(26)00013-9. [Epub ahead of print]128(2): 152328
    Histochemical perspectives on VDAC1-associated autophagy signaling in Alzheimer's disease brain.
    Rajesh Prasad Jayaswal, Kundan Kumar Chaubey, Shanoo Sharma, Manbeer Singh, Kanchan Kholiya.
      
    Keywords:  Alzheimer disease; Autophagy; Histochemistry; Neurodegeneration; Urolithin A; VDAC1
    DOI:  https://doi.org/10.1016/j.acthis.2026.152328
  22. Cells. 2026 Jan 30. pii: 264. [Epub ahead of print]15(3):
    Adipose Tissue-Derived Exosome and miR-142a-3p Alleviate Acute Lung Injury by Inhibiting HMGB1-Driven Autophagy.
    Qianlin Long, Kejie Chen, Yizhu Li, Ruinan Peng, Yijian Yan, Jintao Ma, Jia Wang, Qiuyu Song, Yu Xue, Fengyuan Wang.
      Acute lung injury (ALI) is a clinically severe respiratory disorder, of which autophagy is the crucial mechanism. Exosomes have the potential to treat ALI, but the role of adipose-derived exosomes (ADEs) in the autophagy of ALI remains unclear. Using an LPS-induced ALI model, the effects of ADE isolated from a lean or diet-induced-obese (DIO) mouse and ADE-carried miRNAs were investigated. After administration of ADEs, the levels of autophagy-related molecules were determined by qRT-PCR, Western blotting, and immunohistochemical staining. Then, a miRNA targeting HMGB1 was screened by bioinformatic analysis and a dual-luciferase reporter assay, and its effect on the HMGB1-driven autophagy in an ALI mouse was investigated as ADEs. The data showed that LPS caused lung injury and activated HMGB1-driven autophagy. The ADEs from a lean mouse or DIO mouse significantly alleviated histopathological lesions, and they inhibited HMGB1-driven autophagy by down-regulating LC3, Beclin-1, and Atg5; the effects of ADEs were not significantly different between a lean and DIO mouse. Of the miRNAs carried by ADE, moreover, miR-142a-3p could specifically bind to HMGB1 mRNA, and up-regulation of pulmonary miR-142a-3p suppressed HMGB1-driven autophagy and relieved lung injuries. Our results indicated that miR-142a-3p and ADEs mitigate LPS-induced ALI by inhibiting HMGB1-driven autophagy, providing new insights on the prevention and treatment of ALI.
    Keywords:  acute lung injury; autophagy; exosome; miR-142a-3p
    DOI:  https://doi.org/10.3390/cells15030264
  23. Mol Neurodegener Adv. 2026 ;2(1): 10
    Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis.
    Caroline Ackley, Zoe Liau, Shruti Arya, Tara Antee, Emily Cheang, Giselle M Knudsen, Courtney Lane-Donovan, Paul J Sampognaro, Aimee W Kao.
       Background: The accumulation and aggregation of amyloid beta (A β )-a peptide fragment derived from the proteolytic processing of amyloid precursor protein (APP)-is a central pathological feature of Alzheimer's disease (AD) and a current target for disease-modifying therapies. Mutations in APP can also drive early-onset AD. While the roles of α -, β -, and γ -secretases and their respective cleavage sites in APP processing are well characterized, much less is understood about the routine degradation of APP within sub-cellular compartments like the lysosome.
    Methods: We applied Multiplexed Substrate Profiling by Mass Spectrometry (MSP-MS) to map cleavage sites within APP that may be targeted by lysosomal proteases, also known as cathepsins. We then employed cell-based and in vitro assays to examine the degradation of both wild-type and mutant APP by these enzymes.
    Results: Our findings confirm that APP is enriched in the endo-lysosomal compartment, where it is processed by many cathepsins. Our experiments reveal that cleavages at several mapped APP sites are sensitive to both changes in pH and the presence of pathogenic variants E693G and E693Q. Additionally, we discovered that the large soluble domain of APP (sAPP) enhances tau cleavage by a specific cathepsin, CTSG, in vitro.
    Conclusions: Collectively, these results underscore the importance of lysosomal processing of APP, identify a link between APP and tau, and suggest new avenues for exploring AD pathogenesis. They also highlight potential therapeutic targets related to the lysosomal function of APP and its impact on neurodegenerative diseases.
    Keywords:  Aβ ; APP; Alzheimer’s disease; Amyloid-beta; Amyloid-precursor protein; Autophagy; Cathepsin; Lysosome; Neurodegeneration; Protease; Tau
    DOI:  https://doi.org/10.1186/s44477-025-00017-6
  24. Life Sci. 2026 Feb 10. pii: S0024-3205(26)00078-0. [Epub ahead of print] 124270
    Nucleophagy: The guardian of genome stability - from molecular mechanisms to disease associations.
    Lei Chen, Fen Feng, Qun Zhou, Linxi Chen.
      Nucleophagy is a crucial process by which cells selectively degrade nuclear components through autophagy mechanisms to maintain genomic stability. It occurs through two modes: macro-nucleophagy and micro-nucleophagy, relying on proteins such as Atg39 and Nvj1 to remove irreversibly damaged nuclear components (such as broken chromatin, micronuclei, and abnormal nuclear membrane components) caused by irreversible DNA damage, to degrade toxic nuclear protein aggregates, and to target abnormal nuclear structural components. The activity of nucleophagy is regulated at multiple levels. Transcription factors such as the MiT/TFE family and p53 can sense cellular stress signals to regulate the expression of autophagy genes. Epigenetic mechanisms such as DNA methylation, histone modification, and miRNA participate in the regulation by modifying genes or marking substrates, and these regulatory processes are modulated by signaling molecules and drugs such as mTOR inhibitors. The core function of nucleophagy is to eliminate irreparable damaged nuclear substances, toxic nuclear protein aggregates, and abnormal nuclear structural components, thereby preventing the accumulation of harmful substances. It also exerts a bidirectional regulatory role in pathological processes including cell differentiation, aging, cardiovascular diseases, neurodegenerative diseases, and cancer. Future research needs to further elucidate the regulatory mechanisms of nucleophagy, particularly the crosstalk between transcription factors and epigenetic modifications, as well as the complex connections between nucleophagy and other cellular processes. These studies will provide novel therapeutic targets and strategies for the development of treatments against cancer, neurodegenerative diseases, and cardiovascular diseases, and thus advance the progress of disease treatment and drug development.
    Keywords:  Disease association; Genome stability; Nuclear component clearance; Nucleophagy; Nucleophagy regulation
    DOI:  https://doi.org/10.1016/j.lfs.2026.124270
  25. Mol Med Rep. 2026 Apr;pii: 116. [Epub ahead of print]33(4):
    ULK1 activates NCOA4‑mediated ferritinophagy via the Beclin1/VPS34 complex in cardiomyocyte hypertrophy.
    Qianhui Zhang, Meitian Zhang, Yongsheng Liu, Pilong Shi, Hanping Qi, Man Jiang, Yonggang Cao, Hongli Sun.
      Cardiac hypertrophy is associated with ferroptosis. Serine/threonine protein kinase ULK1 (ULK1) acts as a key activator of autophagy; however, its exact function in the non‑autophagy pathway remains to be fully elucidated. The present study aimed to decipher the role and mechanisms of ULK1 in ferroptosis and cardiomyocyte hypertrophy. Cell survival, lipid peroxidation, iron metabolism and prostaglandin endoperoxide synthase 2 (Ptgs2) mRNA expression were analyzed to investigate the role of ferroptosis in ULK1‑silenced or ULK1‑overexpressing HL‑1 cells. Immunofluorescence staining, western blot analysis and monomeric red fluorescent protein‑green fluorescent protein‑microtubule‑associated protein 1 light chain 3 puncta formation assays were performed to demonstrate the regulatory effect of ULK1 on autophagy and ferritinophagy‑related proteins. Ferritinophagy activation was assessed in cardiomyocytes using immunofluorescence of nuclear receptor coactivator 4 (NCOA4) and microtubule‑associated protein 1 light chain 3‑II colocalization. ULK1 expression was found to be elevated in both transverse aortic constriction‑induced hypertrophic cardiac tissues and angiotensin II‑treated cardiomyocytes. ULK1 knockdown markedly suppressed cardiomyocyte ferroptosis, whereas ULK1 overexpression facilitated ferroptosis in HL‑1 cells. Meanwhile, the ferroptosis inhibitor ferrostatin‑1 reduced iron accumulation, lipid peroxidation and Ptgs2 mRNA expression. Notably, the autophagy inhibitor 3‑methyladenine mitigated ULK1‑induced ferroptosis. Mechanistically, ULK1‑activated NCOA4‑mediated ferritinophagy was found to be dependent on the Beclin1/PI3K catalytic subunit type 3 complex. Finally, the ULK1 inhibitor SBI‑0206965 ameliorated ferroptosis in cardiomyocytes in vitro. For the first time, to the best of our knowledge, the present study demonstrated that ULK1 modulates NCOA4‑mediated ferritinophagy and ferroptosis in HL‑1 cells. The findings of the present study provide a novel insight into the progression of cardiomyocyte hypertrophy.
    Keywords:  Beclin1; ULK1; autophagy; ferritinophagy; ferroptosis
    DOI:  https://doi.org/10.3892/mmr.2026.13826
  26. Sci Adv. 2026 Feb 13. 12(7): eaec5134
    Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism.
    Jamie E Hibbert, Kent W Jorgenson, Ramy K A Sayed, Hector G Paez, Marius Meinhold, Corey G K Flynn, Anthony N Lange, Garrison T Lindley, Philip M Flejsierowicz, Troy A Hornberger.
      Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through a rapamycin-sensitive signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through a rapamycin-insensitive signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of preexisting sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1 but also lay the framework for a revised understanding of the molecular and structural events that drive this process.
    DOI:  https://doi.org/10.1126/sciadv.aec5134
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