bims-auttor 2026-04-26 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–04–26
29 papers selected by
Viktor Korolchuk, Newcastle University

The ubiquitin ligase RNF115 is required for the clearance of damaged lysosomes.
Quantitative analysis of autophagic flux reveals radiation-induced activation of SQSTM1-mediated degradation of protein aggregates and ER-phagy.
Selective autophagy receptors: Multifunctional regulators of organelle turnover.
Autophagy-Lysosomal Axis Stimulation by Beta-Hydroxybutyrate in Astrocytes.
Rab27b: A Modulator of Lysosomal Function and Alpha-Synuclein Clearance in Parkinson's Disease.
The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.
Targeted delivery of glucocerebrosidase to lysosomes: The LYSOTAC (LYSOsome-TArgeting Chimera) technology.
The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.
Getting a handle on RAB1: from Golgi trafficking to mitophagy.
Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.
Prion propagation is controlled by a hierarchical network involving the nuclear Tfap2c and hnRNP K factors and the cytosolic mTORC1 complex.
Coronavirus infectious bronchitis virus spike protein inhibits FUNDC1-mediated mitophagy to prevent nucleocapsid protein degradation.
Lysosomal dysfunction in diabetes and diabetic complications.
Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.
Lysosomal accumulation of Masitinib alters autophagy via pH-dependent trapping.
Pharmacological strategies targeting chaperone-mediated autophagy.
Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
A pressure relief valve for lysosomes.
DeepDrugDiscovery identifies blood-brain barrier permeable autophagy enhancers for Alzheimer's disease.
The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.
mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.
Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
Parkin regulates NLRP3 degradation through chaperone-mediated autophagy to suppress PANoptosis and protect dopaminergic neurons in Parkinson's disease.
Organelle interactome disruption: The systemic pathological mechanisms and therapeutic prospects of mitochondria-lysosome-ER crosstalk in Alzheimer's disease.
Enhanced autophagy drives endothelial tight junction loss, BBB disruption, and behavioral deficits during inflammation.
CLN5 disease-causing mutations impact lysosomal biology by affecting intracellular degradation and protein trafficking.
Pathogenic variants in BORCS5 Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction.
Bacteria use P-body condensates to attenuate host translation during infection.

FEBS Lett. 2026 Apr 24.

The ubiquitin ligase RNF115 is required for the clearance of damaged lysosomes.

Sae Nakanaga, Toshiki Takahashi, Akiko Kuma, Hiroyuki Kawahara.

  Lysosomes play a critical role in the quality control of cellular organelles. However, lysosomal membranes can be damaged under a variety of conditions, leading to the onset of various diseases. Damaged lysosomes are selectively cleared via a ubiquitin-dependent mechanism, but the molecular mechanisms underlying this process have not been adequately elucidated. In this study, we found that RNF115 is a lysosomal damage-responsive ubiquitin ligase that undergoes massive translocation from the cytosol to the p62/SQSTM1-positive puncta around ruptured lysosomes. In accordance with the changes in its distribution, the depletion of RNF115 delayed the removal of Gal3 from damaged lysosomes during the restoration process following lysosomal damage. These observations suggest that RNF115 is responsible for the clearance of damaged lysosomes.

Keywords:  BAG6; E3 ubiquitin ligase; RNF115; autophagy; lysophagy; lysosomal membrane damage; lysosome

DOI:  https://doi.org/10.1002/1873-3468.70346
J Radiat Res. 2026 Apr 22. pii: rrag025. [Epub ahead of print]

Quantitative analysis of autophagic flux reveals radiation-induced activation of SQSTM1-mediated degradation of protein aggregates and ER-phagy.

Takahito Moriwaki, Tsuyoshi Masuda.

  Autophagy is an evolutionarily conserved process that degrades and recycles intracellular components through lysosomes, thereby maintaining cellular homeostasis under stress conditions. Although radiation is known to influence autophagy, most previous studies have relied on static marker expression rather than quantitative evaluation of autophagic flux. In the present study, we quantitatively analyzed autophagic flux in hTERT/RPE-1 cells exposed to γ-rays (0.5-4 Gy) using both bafilomycin A1-based assays and HaloTag reporter systems that visualize lysosomal degradation. LC3-based total autophagic flux remained unchanged even at 4 Gy, indicating that lysosomal function is preserved after irradiation. In contrast, SQSTM1-dependent selective autophagy increased significantly at doses of 2 Gy or higher, suggesting enhanced clearance of radiation-induced protein aggregates. HaloTag-based analyses further revealed that γ-irradiation induced mitophagy and ER-phagy in a dose-dependent manner, consistent with activation of oxidative stress and unfolded protein response pathways. These findings demonstrate that ionizing radiation does not globally suppress autophagy but selectively activates organelle-specific autophagy, particularly SQSTM1-mediated ER-phagy. The selective activation of these quality-control pathways likely contributes to maintaining cellular integrity and stress adaptation following irradiation. Quantitative flux analysis thus provides new insight into the hierarchical regulation of autophagy and its role in cellular survival and repair mechanisms after radiation exposure.

Keywords:  ER-phagy; aggrephagy; autophagy; mitophagy; oxidative stress

DOI:  https://doi.org/10.1093/jrr/rrag025
Curr Opin Cell Biol. 2026 Apr 17. pii: S0955-0674(26)00030-X. [Epub ahead of print]100 102642

Selective autophagy receptors: Multifunctional regulators of organelle turnover.

Akiko Kuma, Tamotsu Yoshimori.

Organelle-selective autophagy (organellophagy) is essential for organelle quality control and cellular homeostasis. Selective degradation of most major organelles has been described and is mediated by specialized autophagy receptors. These receptors were initially defined by their ability to tether target substrates to the growing phagophore through interactions between their LC3-interacting region (LIR) motifs and ATG8 family proteins. Recent studies have expanded this view, revealing that autophagy receptors function as multifunctional regulators. Beyond substrate recognition, they have been shown to promote local concentration of substrates and autophagy factors via liquid-liquid phase separation, actively drive fragmentation of large organelles into autophagosome-compatible sizes, and recruit the autophagy initiation machinery. Together, these findings refine current models of organellophagy and highlight autophagy receptors as central coordinators of organelle turnover.

DOI: https://doi.org/10.1016/j.ceb.2026.102642
Mol Neurobiol. 2026 Apr 21. pii: 573. [Epub ahead of print]63(1):

Autophagy-Lysosomal Axis Stimulation by Beta-Hydroxybutyrate in Astrocytes.

Perla Coronado-Monroy, Teresa Montiel, Lizbeth García-Velázquez, Margarita Zahar-Pérez, Lourdes Massieu.

  Beta-hydroxybutyrate (D-BHB), a ketone body with neuroprotective properties, has been previously shown to increase the autophagic flux in neurons, but its effect on autophagy induction in astrocytes remains unexplored. Astrocyte functionality is essential for neuronal support, and this includes an optimal degradation and recycling of organelles and other cellular components through autophagy. The present study shows that D-BHB exposure to cultured astrocytes elevates the conjugated form of microtubule-associated protein 1A/1B-light chain 3 (LC3-II) levels, increases the number of autophagosomes, and reduces sequestosome-1 (SQSTM1/p62) protein content. D-BHB also enhanced the phosphorylation of AMP-activated kinase (AMPK) and Unc-51-like autophagy activating kinase 1 (ULK1), suggesting increased autophagy initiation. In addition, D-BHB induced the activation of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, increasing the abundance of the lysosomal-associated membrane protein 1 (LAMP1) and lysosomal number. Pharmacological inhibition of Sirtuin 1 (SIRT1) and AMPK/ULK1 activity abated D-BHB-induced increase in LC3-II and SQSTM1/p62 degradation, suggesting that D-BHB-mediated autophagy activation is dependent on the SIRT1/AMPK/ULK1 pathway. Also, results show that D-BHB induction of the autophagy-lysosomal axis improves astrocyte survival under oxygen-glucose deprivation (OGD). Together, the present data suggest that astrocytes, acting as targets of D-BHB, might contribute to the neuroprotective effects of ketone bodies against acute brain injury.

Keywords:  AMP kinase; Ketone bodies; Lysosome biogenesis; mTORC1

DOI:  https://doi.org/10.1007/s12035-026-05852-6
J Neurosci. 2026 Apr 22. pii: e0917252026. [Epub ahead of print]46(16):

Rab27b: A Modulator of Lysosomal Function and Alpha-Synuclein Clearance in Parkinson's Disease.

Rafael A Badell-Grau.



Keywords:  Parkinson's disease; autophagy; lysosomes; neurodegeneration; synapses

DOI:  https://doi.org/10.1523/JNEUROSCI.0917-25.2026
Autophagy. 2026 May;22(5): 877-880

The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.

Dimitra Dialynaki, Daniel J Klionsky.

  Skeletal muscle is a fundamental tissue as it is found throughout the body, sustains posture, and produces movement. Yet, skeletal muscle disorders, such as myopathies, affect a large percentage of the population, degrading an individual's quality of life. A recent study links myopathy progression to the decline in chaperone-mediated autophagy that occurs during aging. Underscoring the importance of a balanced CMA pathway in maintaining skeletal muscle function and integrity, the study also provides mechanistic insights into the pathways that are dysregulated due to defective CMA and presents an approach to reverse the age-dependent decline in this process.Abbreviations: ATP2A1, ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; CMA, chaperone-mediated autophagy; HSPA8, heat shock protein family A (Hsp70) member 8; LAMP2A, lysosomal associated membrane protein 2A.

Keywords:  Aging; calcium homeostasis; chaperone-mediated autophagy; mitochondrial homeostasis; myopathy; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2026.2627051
Asian J Pharm Sci. 2026 Apr;21(2): 101149

Targeted delivery of glucocerebrosidase to lysosomes: The LYSOTAC (LYSOsome-TArgeting Chimera) technology.

Hee-Yeon Kim, Eun Nam Choi, Gee Eun Lee, Sanghwa Yoon, Su Ran Mun, Eui Jung Jung, Minji Kim, Hyomin Lim, Yang Jae Kang, Woo-Jae Park, Yong Tae Kwon, Joo-Won Park.

  Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by misfolding of lysosomal proteins and their degradation via endoplasmic reticulum-associated degradation (ERAD). Deficiency in LSD-associated enzymes leads to the accumulation of toxic materials within the lysosome. In macroautophagy (hereafter autophagy), autophagic receptors as represented by p62/SQSTM1/Sequestosome-1 collect and deliver their cargoes to the lysosome. Here, we developed the LYSOTAC (LYSOsome-TArgeting Chimera) technology, which enables lysosomal targeting of LSD-associated enzymes while preserving their enzymatic activities. LYSOTAC employs a bifunctional chimera that simultaneously binds an LSD-associated enzyme via the enzyme-binding ligand (EBL) and p62 via the autophagy-targeting ligand (ATL). Upon binding, p62 undergoes self-polymerization to form cargo-p62 complexes, which are sequestered into autophagosomes and delivered to lysosomes, where the enzymes exhibit maximal activity. Here, LYSOTAC compounds targeting β-glucocerebrosidase (GCase) were designed to restore GCase activity in lysosomes and promote glucosylceramide degradation in Gaucher disease fibroblasts. We suggest that LYSOTAC provides a potential therapeutic strategy for LSDs.

Keywords:  Autophagy; Gaucher disease; Lysosomal storage diseases; Lysosomal targeting; N-degron pathway; p62/SQSTM1/Sequestosome-1

DOI:  https://doi.org/10.1016/j.ajps.2026.101149
Autophagy. 2026 Apr 23.

The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.

Shu-Q Cao, Juan Ignacio Jiménez-Loygorri, Patricia Boya, Evandro F Fang.

  Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain limited. Emerging evidence suggests that dietary molecules may influence mitochondrial health, although the underlying mechanisms are largely unknown. Here, we summarize our recent finding whereby we have identified a robust mitophagy inducer: α-amyrin (αA). This molecule is a lipid-like pentacyclic triterpenoid abundant in edible plants, such as passion fruit. Mechanistically, αA targets dual leucine zipper kinase (DLK), a neuron-enriched stress kinase that plays a central role in axonal degeneration signaling. Under pathological stress, DLK activates the degeneration mediator SARM1, which can sequester the key autophagy/mitophagy protein ULK1 leading to compromised autophagy and mitophagy. By specifically binding to DLK, αA releases ULK1 from SARM1-mediated restriction and promotes ULK1-dependent mitophagy, restoring mitochondrial homeostasis. This mechanism reveals the DLK-SARM1-ULK1 cascade as a previously underappreciated regulatory interface linking neuronal stress signaling to mitochondrial surveillance pathways. More broadly, these findings introduce lipid-like dietary molecules as potential "mitochondrial guardians" that preserve organelle integrity through physiological activation of mitophagy. Targeting the DLK-SARM1-ULK1 axis with such molecules may represent a promising strategy for maintaining mitochondrial health and mitigating neurodegenerative processes associated with aging.

Keywords:  DLK; ULK1; lipid-like molecule; mitophagy; α-amyrin

DOI:  https://doi.org/10.1080/15548627.2026.2664599
PLoS One. 2026 ;21(4): e0345890

Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.

David K Sidibe, Erin M Smith, Maeve L Spivey, Maria C Vogel, Sandra Maday.

Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.

DOI: https://doi.org/10.1371/journal.pone.0345890
Autophagy. 2026 Apr 21. 1-2

Getting a handle on RAB1: from Golgi trafficking to mitophagy.

Alexander R van Vliet.

  The small GTPase RAB1 is essential for life. A knockout of RAB1 is not only embryonically lethal, but even triggers cell death in a cultured cell line, underscoring its importance for cellular homeostasis. Previous work has shown that RAB1 plays a key role in protein and membrane trafficking as a player in the ER-to-Golgi trafficking pathway. Here, RAB1 has been shown to interact with COPII vesicles that have left the ER and are arriving at the Golgi. In addition, RAB1 is an essential part of autophagy initiation, where loss of RAB1 leads to defects very early in the pathway. To complicate matters further, there is a non-trivial overlap in phenotype between a Golgi trafficking defect and an autophagy initiation problem, as ATG9A vesicle trafficking and the general importance of the Golgi in autophagy illustrates. Given these hurdles, how would one get a handle on the molecular mechanism of RAB1? In this Punctum, I discuss our recent mapping of a new RAB1 interactome that provides fresh insights into its multifaceted functions.

Keywords:  BioID; Golgi; Membrane trafficking; autophagy; interactomics; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2657541
Sci Adv. 2026 Apr 24. 12(17): eaed6824

Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.

Alagie Jassey, Bimal Paudel, Michael A Wagner, Noah Pollack, I-Ting Cheng, Raquel Godoy-Ruiz, David J Weber, William T Jackson.

Enterovirus D68 (EV-D68) is a plus-strand RNA virus that primarily causes respiratory infections in infants but, in rare cases, has been associated with the pediatric paralytic disease acute flaccid myelitis. We previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that the 3C protease of EV-D68 cleaves the mitochondrial fusion protein Mitofusin 2 near its C-terminal HR2 domain, inducing fragmentation of the mitochondrial network. This, in turn, triggers the formation of mitophagosomes, a hallmark of mitophagy, a selective form of autophagy that recycles mitochondria. Multiple hallmarks of mitophagy are observed during infection, including loss of mitochondrial membrane potential and Parkin translocation to the mitochondria, but mitochondrial degradation is blocked during infection. While autophagy plays multiple roles in enterovirus infection, depleting Mitofusin 2 or transiently overexpressing Mitofusin 2, particularly the cleavage-resistant mutant, specifically reduces EV-D68 release from cells without affecting intracellular titers. Our results show that enteroviruses induce mitophagosomes as vectors for nonlytic release of virions from cells.

DOI: https://doi.org/10.1126/sciadv.aed6824
PLoS Pathog. 2026 Apr;22(4): e1014056

Prion propagation is controlled by a hierarchical network involving the nuclear Tfap2c and hnRNP K factors and the cytosolic mTORC1 complex.

Stefano Sellitto, Davide Caredio, Matteo Bimbati, Giovanni Mariutti, Martina Cerisoli, Lukas Frick, Vangelis Bouris, Carlos Omar Oueslati Morales, Dalila Laura Vena, Sandesh Neupane, Federico Baroni, Kathi Ging, Jiang-An Yin, Elena De Cecco, Andrea Armani, Adriano Aguzzi.

Heterogeneous Nuclear Ribonucleoprotein K (hnRNP K) is a limiting factor for prion propagation. However, little is known about the function of hnRNP K except that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify epistatic interactors of HNRNPK. We found that deletion of Transcription Factor AP-2γ (TFAP2C) suppressed the death of hnRNP K-depleted LN-229 and U-251 MG cells, whereas its overexpression hypersensitized cells to hnRNP K loss. HNRNPK ablation decreased cellular ATP, downregulated genes related to lipid and glucose metabolism, and enhanced autophagy. Co-occurrent deletion of TFAP2C reversed these effects, restoring transcriptional balance and alleviating energy deficiency. We linked HNRNPK and TFAP2C functional and genetic interaction to mTOR signaling, observing that hnRNP K depletion inhibited mTORC1 activity through downregulation of mTOR and Rptor, while TFAP2C overexpression enhanced mTORC1 downstream functions. In prion-infected cells, TFAP2C activation reduced prion levels and countered the increased prion propagation caused by HNRNPK suppression. Short-term inhibition of mTORC1 also elevated prion levels and partially mimicked the effects of HNRNPK silencing. Our study identifies TFAP2C as a genetic interactor of HNRNPK, implicates their roles in mTOR metabolic regulation, and establishes a causative link between these activities and prion propagation.

DOI: https://doi.org/10.1371/journal.ppat.1014056
J Virol. 2026 Apr 20. e0180025

Coronavirus infectious bronchitis virus spike protein inhibits FUNDC1-mediated mitophagy to prevent nucleocapsid protein degradation.

Jun Zhao, Jiaxin Tian, Liwei Zhang, Yingfei Li, Lihua Tang, Qila Sa, Ruotong Li, Jing Zhao, Ye Zhao, Guozhong Zhang.

  Autophagy is involved in various stages of the viral life cycle and modulates viral replication. Coronaviruses have developed several strategies to exploit autophagy for their benefit. Nevertheless, the exact mechanisms through which the infectious bronchitis virus (IBV) influences autophagy remain inadequately understood. Here, we demonstrate that IBV infection of chicken embryonic kidney (CEK) cells activates the AKT-mTOR signaling pathway to suppress autophagosome formation and mitophagy. Further investigation reveals that the viral spike protein (S) inhibits cellular autophagy by interacting with the mitophagy receptor FUNDC1. However, FUNDC1-mediated mitophagy promotes degradation of the viral nucleocapsid (N) protein and restricts IBV replication. To counteract this host defense mechanism, the S protein competitively binds to the LC3-interacting region (LIR) motif of FUNDC1, thereby disrupting its interaction with LC3 and ultimately suppressing mitophagy. Molecular docking analysis revealed that a conserved asparagine residue at position 240 (N240) in the S1 subunit of the IBV S protein is essential for binding to FUNDC1. Furthermore, reverse genetics demonstrated that an IBV mutant with an N240A substitution exhibited reduced pathogenicity in the kidneys, trachea, and lungs of specific-pathogen-free (SPF) chickens compared to the wild-type virus. Collectively, these findings unveil a novel mechanism by which IBV antagonizes host mitophagy and provide new insights into the host-virus interplay within the context of autophagic regulation.IMPORTANCEIBV has evolved a mechanism to counteract the host's antiviral defense. Specifically, the viral spike (S) protein blocks a form of autophagy called mitophagy by binding to the mitochondrial receptor FUNDC1. Normally, FUNDC1 helps cells eliminate damaged mitochondria and restricts IBV replication by promoting the degradation of the viral nucleocapsid protein. By interfering with this process, the S protein enhances viral survival. We further identified a single conserved amino acid in the S protein that is critical for this function, and mutation of this residue weakened IBV in chickens. These findings reveal how IBV manipulates host defenses and suggest new strategies for controlling coronavirus infections.

Keywords:  FUNDC1; IBV; host-virus; mitophagy; spike protein

DOI:  https://doi.org/10.1128/jvi.01800-25
Front Endocrinol (Lausanne). 2026 ;17 1794600

Lysosomal dysfunction in diabetes and diabetic complications.

Xin Chen, Lishan Huang, Zhiwen Xiao, Libin Liu.

  Lysosomes, as organelles with degradative, secretory and signaling functions in eukaryotic cells, play a pivotal role in maintaining cellular energy homeostasis and biological recycling processes. In recent years, lysosomal dysfunction has garnered extensive attention from scholars for its implications in neurodegenerative and autoimmune diseases. however, its role in the occurrence and progression of diabetes mellitus and its complications remains to be further explored. Therefore, this article summarizes the research progress on lysosomal dysfunction in diabetes and its complications, hoping to highlight a promising therapeutic direction.

Keywords:  autophagy; diabetes; diabetic complications; lysosomal; lysosomal dysfunction

DOI:  https://doi.org/10.3389/fendo.2026.1794600
Biochem Biophys Rep. 2026 Jun;46 102571

Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.

Christina Keller, Sebastian Rading, Bahar Candur, Laura Bindila, Gabriele Loers, Meliha Karsak.

  The endocannabinoid system (ECS) and the autophagy receptor p62 are both implicated in metabolic regulation and obesity, yet the mechanisms linking these pathways remain unclear. Here, we investigated whether p62 modulates CB1 receptor (CB1R) turnover or function and whether CB1R contributes to the metabolic phenotype of p62 knockout (KO) mice. In primary cortical neurons from wild-type mice, inhibition of autophagic flux with Bafilomycin A1 led to substantial CB1R accumulation, demonstrating that CB1R is a subject to autophagy-dependent degradation. CB1R agonist stimulation partially reduced this accumulation, suggesting receptor activation influences turnover. In vivo, p62 deficiency did not significantly alter CB1R protein abundance in the brain or hypothalamus, although hypothalamic ERK1/2 signaling downstream of CB1R was modestly attenuated. P62 KO mice displayed late-onset obesity without hyperphagia, early hypoactivity, and elevated hypothalamic 2-arachidonoylglycerol (2-AG) levels with age. Fasting-refeeding experiments revealed reduced food intake in adult and aged, but not juvenile, p62 KO animals. Pharmacological CB1R antagonism did not uncover a direct receptor-dependent mechanism underlying these phenotypes. Together, these findings indicate that, although CB1R undergoes autophagic degradation in neurons, p62 deficiency does not alter steady-state receptor levels and does not directly account for obesity or hypoactivity in p62 KO mice. Within the scope of the experiments performed, CB1R is therefore unlikely to be a primary driver of the metabolic phenotype associated with p62 deficiency.

Keywords:  Autophagy; CB1 receptor; Endocannabinoid system; Fasting; Locomotor activity; Obesity; p62

DOI:  https://doi.org/10.1016/j.bbrep.2026.102571
Eur J Pharmacol. 2026 Apr 18. pii: S0014-2999(26)00354-7. [Epub ahead of print] 178872

Lysosomal accumulation of Masitinib alters autophagy via pH-dependent trapping.

Abdulrahman El Sayed, Monika Kluzek, Remigiusz Serwa, Abdelhalim Azzi.

  Small-molecule kinase inhibitors often exhibit complex cellular behaviors that cannot be explained solely by target inhibition. Masitinib is a clinically investigated tyrosine kinase inhibitor with reported anti-inflammatory and neuroprotective effects, yet its intracellular mechanism of action remains poorly defined. Here, we show that masitinib undergoes pH-dependent lysosomal sequestration that dominates its cellular activity. Across multiple cell lines, masitinib suppresses mTORC1 signaling while paradoxically inducing AKT phosphorylation through a VPS34 and rapamycin-sensitive pathway independent of class I PI3K. Thermal proteome profiling identifies lysosomal proteins as the primary off-target signature of masitinib. Using defined membrane model systems that recapitulate lysosomal lipid composition and acidity, we demonstrate that masitinib preferentially accumulates and intercalates into acidic, negatively charged membranes. This lysosomal accumulation impairs lysosomal acidification and disrupts autophagic flux, providing a mechanistic link between the physicochemical properties of masitinib and its downstream signaling effects. Together, our findings highlight lysosomal sequestration as a key determinant of kinase inhibitor behavior and underlie the importance of subcellular drug distribution in modulating cellular responses.

Keywords:  GUVs; LUVs; Masitinib; autophagy; lysosome trapping

DOI:  https://doi.org/10.1016/j.ejphar.2026.178872
Trends Pharmacol Sci. 2026 Apr 20. pii: S0165-6147(26)00084-2. [Epub ahead of print]

Pharmacological strategies targeting chaperone-mediated autophagy.

Eva Berenger, Alice Maestri, Daniel R Vaz, Elena Kochetkova, Erik Norberg, Vitaliy O Kaminskyy, S Joseph Endicott, Helin Vakifahmetoglu-Norberg.

  Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradation pathway that regulates proteostasis, metabolism, and stress adaptation. Genetic- and disease-model studies show that altered CMA activity contributes to diverse human disorders, including neurodegenerative, metabolic, inflammatory, and malignant diseases. However, pharmacological targeting has remained challenging due to a limited understanding of its regulatory architecture and a lack of criteria to distinguish pathway-selective from indirect modulation. Recent advances in mapping CMA regulatory checkpoints and the in vivo validation of CMA-biased compounds have revealed discrete, mechanistically defined control nodes that render CMA pharmacologically tractable. In this review, we synthesize these advances and introduce a mechanistic classification of CMA-modulating compounds by level of action, distinguishing physiological inducers, permissive potentiators, and proximal activators to clarify pathway selectivity and guide translational drug discovery.

Keywords:  LAMP-2A; chaperone-mediated autophagy; pharmacological modulation; proteostasis; therapeutic targeting

DOI:  https://doi.org/10.1016/j.tips.2026.03.008
Autophagy. 2026 Apr 23. 1-15

Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.

Madhuri Chaurasia, Milana Fraiberg, Nemanja Subic, Oren Shatz, Kamilya Kokabi, Olee Gogoi, Olena Trofimyuk, Bat Chen Tamim-Yecheskel, Saskia Freud, Alik Demishtein, Ekaterina Kopitman, Inna Goliand, Sabita Chourasia, Yoav Peleg, Elena Ainbinder, Nili Dezorella, Zvulun Elazar.

  HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the TECPR2 gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.Abbreviations: Baf. A1: bafilomycin A1; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.

Keywords:  HSAN9; TECPR2; integrated stress response; mitophagy; neurodegeneration; unfolded protein response

DOI:  https://doi.org/10.1080/15548627.2026.2660850
J Cell Biol. 2026 May 04. pii: e202604009. [Epub ahead of print]225(5):

A pressure relief valve for lysosomes.

Layla M Nassar, Shawn M Ferguson.

Several mechanisms repair damaged lysosomal membranes, but how can lysosomes prevent membrane failure in the first place? Kim et al. (https://doi.org/10.1083/jcb.202509180) uncover a rapid response whereby TMEM63A-dependent ion efflux relieves membrane tension, buying time for slower repair mechanisms to engage.

DOI: https://doi.org/10.1083/jcb.202604009
Nat Biomed Eng. 2026 Apr 24.

DeepDrugDiscovery identifies blood-brain barrier permeable autophagy enhancers for Alzheimer's disease.

Yu Dong, Xianglu Xiao, Xu-Xu Zhuang, Wenfan Wu, Zi-Ying Wang, Shuang Zhang, Jin-Tao Li, Ke Zhang, Wen-Yu Fu, Jun-Ming Chen, Shi Hang Xiong, Shenglong Deng, Krinos Li, Chao Ma, Wangzhen Jin, Xurui Jin, Qiwei Cai, Han-Ming Shen, Min Li, Huanxing Su, Jian-Bo Wan, Hua Yu, Defang Ouyang, Keqiang Ye, Evandro F Fang, Chris Soon Heng Tan, Guang Yang, Zhangming Niu, Jia-Hong Lu.

Dysfunctional autophagy, a key cellular cleaning process, is a key driver of brain ageing and neurodegenerative diseases such as Alzheimer's disease (AD). However, developing effective treatments by enhancing autophagy has been challenging, as most known compounds act through the broad mTOR pathway, risking side effects, and few can effectively penetrate the brain. To address this, we developed DeepDrugDiscovery-a mechanism-aware, AI-powered screening platform incorporating ADMET and blood-brain barrier penetrability predictions. Here we show that this platform successfully identified novel, mTOR-independent autophagy enhancers, with two lead compounds demonstrating an ability to cross the blood-brain barrier, clear AD-related protein aggregates and restore memory function in worm and mouse AD models. By releasing DeepDrugDiscovery as an open-source, modular tool, we offer a user-friendly AI platform that enables customized therapeutic screening. Our work establishes a scalable, AI-driven pipeline that integrates cross-species validation to rapidly discover mechanism-based therapeutics for diseases with high unmet medical need.

DOI: https://doi.org/10.1038/s41551-026-01667-x
Toxicol Res. 2026 May;42(3): 325-343

The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.

Eun-Ji Choi, Sang-Min Jeon.

  Sequestosome 1 (SQSTM1/p62), long established as a selective autophagy receptor and ubiquitin-binding scaffold, is now recognized as an emerging regulatory hub that integrates signaling, metabolism, and stress adaptation in cancer. Beyond its canonical role in proteostatic cargo degradation, recent advances have revealed that p62 orchestrates nutrient sensing, redox control, innate immune signaling, and metabolic reprogramming through highly dynamic, context-dependent mechanisms. A nascent paradigm emerging from recent studies is that p62 function is specified by a hierarchical post-translational modification (PTM) code, with phosphorylation acting as the primary regulatory layer. Site-specific phosphorylation events-together with modulatory PTMs such as S-acylation, arginine methylation, and O-GlcNAcylation-reshape p62 interaction networks, liquid-liquid phase separation (LLPS) behavior, and signaling output. Through these mechanisms, p62 operates as a sophisticated signal-metabolism interface that couples stress signaling pathways, including NFE2L2/NRF2, AMPK, mTORC1, and NF-κB to the systemic rewiring of glucose, lipid, amino acid, and nucleotide metabolism. Notably, a phosphorylation-dependent positive feedback loop between p62 and AMPK has emerged as a key driver of metabolic plasticity, enabling tumor cells to survive and proliferate under the stringent metabolic stress conditions of the tumor microenvironment. This review integrates recent mechanistic insights into the PTMs, phase behavior, and signaling hub functions of p62, highlighting how these principles manifest in distinct oncogenic contexts, such as lung, prostate, and brain tumors. We further discuss emerging therapeutic strategies that seek to modulate p62-centered assemblies rather than indiscriminately inhibit p62 function. Collectively, these findings position p62 as a phosphorylation-governed oncogenic nexus whose precise manipulation may enable new strategies for context-dependent precision oncology.

Keywords:  AMPK; Cancer; Metabolism; NFE2L2/NRF2; SQSTM1/P62; Signaling

DOI:  https://doi.org/10.1007/s43188-026-00349-9
Sci Signal. 2026 Apr 21. 19(934): eadu5769

mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.

Keita Uchida, Emily A Scarborough, Elizabeth Pruzinsky, Kathlyene R Stone, Hali Hartman, Daniel P Kelly, Jonathan J Edwards, Izhak Kehat, Benjamin L Prosser.

Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK-dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK-dependent phosphorylation of 4EBP1 at Ser64 was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.

DOI: https://doi.org/10.1126/scisignal.adu5769
Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166

Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.

Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.

  Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.

Keywords:  Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes

DOI:  https://doi.org/10.1016/j.redox.2026.104166
J Neuroinflammation. 2026 Apr 22.

Parkin regulates NLRP3 degradation through chaperone-mediated autophagy to suppress PANoptosis and protect dopaminergic neurons in Parkinson's disease.

Dongyan Zheng, He Zhang, Ailun Xie, Huilin Xiao, Duanqin Guan, Zhefan Xie, Jiankun Luo, Jianwei Cao, Tianji Lin, Lifei Xing, TingTing Xia, Fei Zou, Jialong Chen.

  Parkinson's Disease (PD) is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PANoptosis, a programmed inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, contributes to DA neuron degeneration in PD. The E3 ubiquitin ligase Parkin and the inflammasome sensor NOD-like receptor protein 3 (NLRP3) are known to play critical regulatory roles in DA neuron degeneration. However, whether Parkin modulated NLRP3 via chaperone-mediated autophagy (CMA) to inhibit PANoptosis remained unclear. To verify the above hypothesis, SN4741 cells and C57BL/6 mice were treated with rotenone to establish PD models. PANoptosis activation and DA neurons degeneration were observed in PD models, and these pathological manifestations were mitigated by the NLRP3 inhibitor MCC950. Besides, Parkin interacted with NLRP3, ubiquitinated its K353 residue, and then promoted NLRP3 degradation via CMA. Parkin overexpression or CMA activation alleviated DA neuron damage and PANoptosis, while K353R mutation abolished these effects. It was revealed that Parkin mediated CMA-dependent degradation of NLRP3 (targeting K353) to suppress PANoptosis and protect DA neurons in PD. CMA activators or NLRP3 inhibitors may serve as disease-modifying therapies for PD.

Keywords:  Chaperone-mediated autophagy; Dopaminergic neuron; NLRP3; PANoptosis; Parkin; Parkinson’s disease

DOI:  https://doi.org/10.1186/s12974-026-03814-2
Ageing Res Rev. 2026 Apr 21. pii: S1568-1637(26)00137-6. [Epub ahead of print]118 103145

Organelle interactome disruption: The systemic pathological mechanisms and therapeutic prospects of mitochondria-lysosome-ER crosstalk in Alzheimer's disease.

Liping Xing, Annan Liu, Wei Gao, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.

  The traditional pathological framework of Alzheimer's disease (AD) primarily focuses on the accumulation of β-amyloid (Aβ) and tau proteins. However, therapeutic strategies targeting these molecules have repeatedly encountered setbacks in clinical translation. Recent studies have progressively revealed that the dynamic interaction network among intracellular organelles plays a central role in the pathogenesis of AD. This systematic review examines the independent dysfunctions of three key organelles-mitochondria, lysosomes, and the endoplasmic reticulum (ER)-in AD, along with their physical and functional connectivity mechanisms. It emphasizes how their interaction network, formed through membrane contact sites, synergistically drives core AD pathological processes, including calcium signaling dysregulation, Aβ metabolism imbalance, mitochondrial quality control failure, lipid metabolism disorders, and neuroinflammation with apoptosis. This paper innovatively proposes that AD can be regarded as a "mitochondrial network disorder," the pathological essence of which lies in the systemic breakdown of communication between mitochondria. Building on this premise, we further discuss a therapeutic strategy centered on mitophagy enhancers to reshape the mitochondrial network and explore the translational medical prospects of achieving multi-target synergistic intervention by restoring the homeostasis of the mitochondrial network.

Keywords:  Alzheimer's disease; Endoplasmic reticulum stress; Lysosomal dysfunction; Membrane contact sites; Mitochondrial-endoplasmic reticulum connections; Organelle interaction networks

DOI:  https://doi.org/10.1016/j.arr.2026.103145
Autophagy. 2026 Apr 19.

Enhanced autophagy drives endothelial tight junction loss, BBB disruption, and behavioral deficits during inflammation.

Milin Peng, Wei Chen, Qingtao Gao, Xuejing Zhu, Laidong Yu, Lin Zhang, Xinying Zou, Zhonghua Hu, Lina Zhang.

  The blood-brain barrier (BBB) protects the brain but becomes compromised during systemic inflammatory conditions such as sepsis. The mechanisms driving BBB disruption remain incompletely understood. Here, we identified a significant enrichment of the macroautophagy/autophagy-lysosome-related pathway in the upregulated proteome using quantitative proteomics on brain microvessels from mice after cecal ligation and puncture (CLP) that induces polymicrobial sepsis. CLP progressively induced autophagic flux in brain endothelial cells, peaking at 24 h post-procedure before subsiding. Similarly, an mRFP-GFP-LC3 reporter assay and immunoblotting showed that lipopolysaccharide (LPS) treatment increased autophagic flux in bEnd.3 cells in a time- and dose-dependent manner. Mice intraperitoneally (IP) injected with the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA) were resistant to BBB disruption caused by CLP or IP injection of LPS, whereas those injected with the autophagy inducer rapamycin (Rapa) were more susceptible. CQ and 3-MA reduced, while Rapa increased, CLP-induced lethality in mice. These effects were confirmed in vitro using a dextran infiltration assay on bEnd.3 cell transwell cultures. CQ alleviated both the acute disruption of the tight junction proteins TJP1/ZO-1 and CLDN5 in brain microvessels and the long-term memory and anxiety deficits in LPS-challenged mice. siRNA-mediated knockdown of the SNARE protein STX17, which inhibits autophagosome-lysosome fusion, attenuated LPS-induced tight junction protein degradation in bEnd.3 cells. Importantly, inhibition of TLR4 or its downstream kinase TBK1 reduced LPS-induced autophagy and preserved tight junction proteins, implicating TLR4-TBK1 signaling in endothelial autophagy activation. These results suggest that excessive autophagy in endothelial cells drives BBB damage and cognitive dysfunction in sepsis.

Keywords:  Autophagy; blood-brain barrier; brain endothelial cell; sepsis; tight junction

DOI:  https://doi.org/10.1080/15548627.2026.2662440
Biochim Biophys Acta Mol Basis Dis. 2026 Apr 22. pii: S0925-4439(26)00136-5. [Epub ahead of print] 168273

CLN5 disease-causing mutations impact lysosomal biology by affecting intracellular degradation and protein trafficking.

William D Kim, Samer A Owiar, Cassandra H Pyne, Stéphane Lefrançois, Robert J Huber.

  Ceroid lipofuscinosis neuronal 5 (CLN5) disease is a subtype of neuronal ceroid lipofuscinosis (NCL, commonly known as Batten disease) that is caused by mutations in the CLN5 gene. While 70 distinct CLN5 disease-causing mutations have been documented, the pathological effects of these mutations are largely unknown. In this study, we used the model eukaryote Dictyostelium discoideum to examine the molecular and cellular effects of five CLN5 disease-causing mutations (p.Cys77Tyr, p.Trp158Ser, p.Tyr209Asp, p.Glu303*, and p.Tyr343*). We used informatics tools to show that the five mutations alter the predicted structure of the protein. We then introduced these mutations into Dictyostelium Cln5 and examined their effects on the localization and secretion of the protein, as well as proteostasis and lysosomal activity. We observed that the mutations alter the cellular distribution of Cln5 and intracellular catabolic mechanisms, including 20S proteasome-mediated protein degradation and lysosomal enzyme-mediated breakdown. The mutations also affect vesicles within the endo-lysosome pathway and the release of Cln5 and other lysosomal enzymes from cells, which impacts extracellular enzyme activity. Finally, while cell proliferation and aggregation were not affected by mutated Cln5, loss of the signal peptide in Cln5 delayed aggregation, suggesting an extracellular role for the protein. This study, which is the first to comprehensively examine the effects of the p.Cys77Tyr, p.Trp158Ser, p.Tyr209Asp, p.Glu303*, and p.Tyr343* mutations on cellular function, enhances our understanding of the effects of mutations in CLN5 on endo-lysosomal trafficking and lysosomal biology, as well as the pathological mechanisms underlying CLN5 disease.

Keywords:  CLN5; Catabolism; Dictyostelium; Enzyme activity; Lysosomes; Mutation; Secretion

DOI:  https://doi.org/10.1016/j.bbadis.2026.168273
J Clin Invest. 2026 Apr 21. pii: e195336. [Epub ahead of print]

Pathogenic variants in BORCS5 Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction.

Niccolò E Mencacci, Georgia Minakaki, Reza Maroofian, Raffaella De Pace, Adeline Paimboeuf, Tiago Branco Fonseca, Tatiana Abramova, Patrick Shannon, David Chitayat, Francesca Magrinelli, Wesley J Peng, Diptaman Chatterjee, Sara H Eldessouky, Julia Baptista, Tamas Marton, Julie Vogt, Juan Dario Ortigoza-Escobar, Loreto Martorell, Marta Gómez-Chiari, Ingrid M Wentzensen, Erik-Jan Kamsteeg, Maha S Zaki, Annarita Scardamaglia, Giovanni Zifarelli, Zuhair Nasser Al-Hassnan, Elka Miller, Shiri Shinar, Lova S Matsa, Sri Hari Chandan Appikonda, Ghada A Otaify, Khalid Al-Thihli, Almundher Al-Maawali, Michael Schwake, Mariasavina Severino, Henry Houlden, Shunmoogum A Patten, Juan S Bonifacino, Kailash P Bhatia, Dimitri Krainc.

  BORCS5 encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from nine families with bi-allelic BORCS5 variants, revealing a spectrum of neurodevelopmental and neurodegenerative phenotypes. Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and increased seizure susceptibility, mirroring the patients' clinical presentation. At the cellular level, only BORCS5 PTVs, but not missense variants, led to perinuclear lysosomal clustering and impaired lysosomal axonal trafficking in induced pluripotential stem cell-derived forebrain neurons. However, both PTVs and missense variants were associated with reduced lysosomal proteolysis and activity of lysosomal hydrolases glucocerebrosidase and cathepsin B, indicating lysosomal dysfunction. Our study reveals a role for BORCS5 in modulation of lysosomal function, in addition to its known role in lysosome movement and fusion, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.

Keywords:  Cell biology; Genetics; Lysosomes; Neurodegeneration; Neurodevelopment; Neuroscience

DOI:  https://doi.org/10.1172/JCI195336
Sci Adv. 2026 Apr 24. 12(17): eaec4477

Bacteria use P-body condensates to attenuate host translation during infection.

Manuel González-Fuente, Nico Schulz, Alibek Abdrakhmanov, Thorben Krüger, Gaiea Izzati, Shanshuo Zhu, Gautier Langin, Paul Gouguet, Mirita Franz-Wachtel, Boris Macek, Anders Hafrén, Yasin Dagdas, Suayib Üstün.

Pathogens use sophisticated strategies to modulate host protein homeostasis by targeting proteolytic pathways, but their impact on protein synthesis remains elusive. We report that pathogenic bacteria Pseudomonas syringae (Pst) targets ribonucleoprotein condensates, known as processing bodies (P-bodies), to attenuate host translation through two effectors with liquid-like properties. We uncovered a previously unknown link that Pst-mediated repression of the endoplasmic reticulum stress response is required for P-body assembly. Furthermore, we identify a functional link between P-bodies and autophagy, demonstrating that autophagic clearance of P-bodies is crucial for maintaining the balance between translationally active and inactive messenger RNAs. Together, our findings provide insights on how host translation is attenuated by bacteria to dampen plant immunity and uncover unknown connections between ER stress responses and autophagy with P-body dynamics.

DOI: https://doi.org/10.1126/sciadv.aec4477