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Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage.

ABSTRACT: We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently of SG condensates whereupon NUFIP2 contributed to mTOR inactivation via the Ragulator-RagA/B complex. Thus, cells employ membrane atg8ylation to control and coordinate SG and mTOR responses to lysosomal damage.

SUBMITTER: Jia J

PROVIDER: S-EPMC9533235 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage.

Jia Jingyue J Wang Fulong F Bhujabal Zambarlal Z Peters Ryan R Mudd Michal M Duque Thabata T Allers Lee L Javed Ruheena R Salemi Michelle M Behrends Christian C Phinney Brett B Johansen Terje T Deretic Vojo V

The Journal of cell biology 20220930 11

We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes ...[more]

PMID: 36179369

Similar Datasets

Membrane atg8ylation coordinates stress granule formation and mTOR inactivation in response to lysosomal damage

Project description:We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently of SG condensates whereupon NUFIP2 contributed to mTOR inactivation via the Ragulator-RagA/B complex. Thus, cells employ membrane atg8ylation to control and coordinate SG and mTOR responses to lysosomal damage.

2022-06-09 | MSV000089622 | MassIVE

ATG8ylation of vacuolar membrane protects plants against cell wall damage.

Project description:Vacuoles are essential for cellular metabolism and growth and the maintenance of internal turgor pressure. They sequester lytic enzymes, ions and secondary metabolites that, if leaked into the cytosol, could lead to cell death. Despite their pivotal roles, quality control pathways that safeguard vacuolar integrity have remained elusive in plants. Here we describe a conserved vacuolar quality control pathway that is activated upon cell wall damage in a turgor-pressure-dependent manner. Cell wall perturbations induce a distinct modification-ATG8ylation-on the vacuolar membrane (tonoplast) that is regulated by the V-ATPase and ATG8 conjugation machinery. Genetic disruption of tonoplast ATG8ylation impairs vacuolar integrity, leading to cell death. Together, our findings reveal a homeostatic pathway that preserves vacuolar integrity upon cell wall damage.

| S-EPMC11842276 | biostudies-literature

Atg8ylation coordinates stress granule formation and mTOR inactivation in response to lysosomal damage

Project description:Stress granule formation is a part of cellular homeostatic responses, with prototypical inducers being viral infections, heat shock and oxidative damage. Here we show that lysosomal damage is a previously unappreciated robust inducer of stress granule formation interlinked with mTOR inactivation during lysosomal damage. We find the two processes to be coordinated by a non-autophagy function of mammalian Atg8 proteins (mAtg8s). Stress granules were induced in response to biochemical damage and diverse lysosome damaging biological agents including SARS-CoV-2 ORF3a, Mycobacterium tuberculosis and protopathic tau. Proteomic analyses of purified lysosomes subjected to biochemical damage revealed recruitment to lysosomes of a network of stress granule proteins, including G3BP1 and NUFIP2. G3BP1 and NUFIP2 contributed to inactivation of mTOR during lysosomal damage via the Ragulator-RagA/B system. Lysosomal damage recruited a subset of mAtg8s commonly related to autophagy but also known to associate with other stressed or remodeling membranes. The GABARAP subset of mAtg8s interacted with G3BP1 and NUFIP2 and were required for NUFIP2 and G3BP1 recruitment to the damaged lysosomes. GABARAPs acted as a switch between the utilization of G3BP1 and NUFIP2 in stress granule formation vs. their role in mTOR inactivation. We furthermore found that mAtg8s lipidation, referred herein as Atg8ylation to distinguish it from its conventional implication in autophagy, but not the canonical autophagy factors ATG13, FIP200, and ATG9A, favored mTOR inactivation during lysosomal damage vs. the stress granule formation. Thus, cells utilize Atg8ylation as a response to membrane stress for specific outcomes beyond the process of autophagy, which include the coordinated stress granule formation and mTOR inactivation during lysosomal damage

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Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress.

Project description:The exact roles of lysosomal membrane permeabilization (LMP) in oxidative stress-triggered apoptosis are not completely understood. Here, we first studied the temporal relation between LMP and mitochondrial outer membrane permeabilization (MOMP) during the initial stage of apoptosis caused by the oxidative stress inducer H2O2. Despite its essential role in mediating apoptosis, the expression of the BH3-only Bcl-2 protein Noxa was dispensable for LMP. In contrast, MOMP was dependent on Noxa expression and occurred downstream of LMP. When lysosomal membranes were stabilized by the iron-chelating agent desferrioxamine, H2O2-induced increase in DNA damage, Noxa expression, and subsequent apoptosis were abolished by the inhibition of LMP. Importantly, LMP-induced Noxa expression increase was mediated by p53 and seems to be a unique feature of apoptosis caused by oxidative stress. Finally, exogenous iron loading recapitulated the effects of H2O2 on the expression of BH3-only Bcl-2 proteins. Overall, these data reveal a Noxa-mediated signaling pathway that couples LMP with MOMP and ultimate apoptosis during oxidative stress.

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Restoration of lysosomal function after damage is accompanied by recycling of lysosomal membrane proteins.

Project description:Lysosomes are central organelles for cellular degradation and energy homeostasis. In addition, lysosomal membrane permeabilization (LMP) and subsequent release of lysosomal content to the cytosol can initiate programmed cell death. The extent of LMP and available repair mechanisms determine the cell fate after lysosomal damage. In this study, we aimed to investigate the premises for lysosomal membrane repair after LMP and found that lysosomal membrane damage initiated by L-leucyl-L-leucine methyl ester (LLOMe) caused caspase-dependent apoptosis in almost 50% of the cells, while the rest recovered. Immediately after LLOMe addition, lysosomal proteases were detected in the cytosol and the ESCRT-components ALIX and CHMP4B were recruited to the lysosomal membrane. Next, lysophagic clearance of damaged lysosomes was evident and a concentration-dependent translocation of several lysosomal membrane proteins, including LAMP2, to the cytosol was found. LAMP2 was present in small vesicles with the N-terminal protein chain facing the lumen of the vesicle. We conclude that lysophagic clearance of damaged lysosomes results in generation of lysosomal membrane protein complexes, which constitute small membrane enclosed units, possibly for recycling of lysosomal membrane proteins. These lysosomal membrane complexes enable an efficient regeneration of lysosomes to regain cell functionality.

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A guide to membrane atg8ylation and autophagy with reflections on immunity.

Project description:The process of membrane atg8ylation, defined herein as the conjugation of the ATG8 family of ubiquitin-like proteins to membrane lipids, is beginning to be appreciated in its broader manifestations, mechanisms, and functions. Classically, membrane atg8ylation with LC3B, one of six mammalian ATG8 family proteins, has been viewed as the hallmark of canonical autophagy, entailing the formation of characteristic double membranes in the cytoplasm. However, ATG8s are now well described as being conjugated to single membranes and, most recently, proteins. Here we propose that the atg8ylation is coopted by multiple downstream processes, one of which is canonical autophagy. We elaborate on these biological outputs, which impact metabolism, quality control, and immunity, emphasizing the context of inflammation and immunological effects. In conclusion, we propose that atg8ylation is a modification akin to ubiquitylation, and that it is utilized by different systems participating in membrane stress responses and membrane remodeling activities encompassing autophagy and beyond.

| S-EPMC9202678 | biostudies-literature

ATG8ylation of proteins: A way to cope with cell stress?

Project description:The ATG8 family of proteins regulates autophagy in a variety of ways. Recently, ATG8s were demonstrated to conjugate directly to cellular proteins in a process termed "ATG8ylation," which is amplified by mitochondrial damage and antagonized by ATG4 proteases. ATG8s may have an emerging role as small protein modifiers.

| S-EPMC8532562 | biostudies-literature

Stress granules are dispensable for mRNA stabilization during cellular stress.

Project description:During cellular stress, protein synthesis is severely reduced and bulk mRNA is recruited to stress granules (SGs). Previously, we showed that the SG-recruited IGF2 mRNA-binding protein 1 (IGF2BP1) interferes with target mRNA degradation during cellular stress. Whether this requires the formation of SGs remained elusive. Here, we demonstrate that the sustained inhibition of visible SGs requires the concomitant knockdown of TIA1, TIAR and G3BP1. FRAP and photo-conversion studies, however, indicate that these proteins only transiently associate with SGs. This suggests that instead of forming a rigid scaffold for mRNP recruitment, TIA proteins and G3BP1 promote SG-formation by constantly replenishing mRNPs. In contrast, RNA-binding proteins like IGF2BP1 or HUR, which are dispensable for SG-assembly, are stably associated with SGs and the IGF2BP1/HUR-G3BP1 association is increased during stress. The depletion of IGF2BP1 enhances the degradation of target mRNAs irrespective of inhibiting SG-formation, whereas the turnover of bulk mRNA remains unaffected when SG-formation is impaired. Together these findings indicate that the stabilization of mRNAs during cellular stress is facilitated by the formation of stable mRNPs, which are recruited to SGs by TIA proteins and/or G3BP1. Importantly, however, the aggregation of mRNPs to visible SGs is dispensable for preventing mRNA degradation.

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Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function.

Project description:ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here we show that ATG5 associates with retromer's core components VPS26, VPS29 and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors.

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Tellurite Promotes Stress Granules and Nuclear SG-Like Assembly in Response to Oxidative Stress and DNA Damage.

Project description:Tellurium oxyanion, tellurite (TeO 3 -2), is a highly toxic compound for many organisms. Its presence in the environment has increased over the past years due to industrial manufacturing processes and has been associated with adverse effects on human health. Although tellurite induces the phosphorylation of eIF2α, DNA damage and oxidative stress, the molecular mechanisms related to the cellular responses to tellurite-induced stress are poorly understood. In this work, we evaluated the ability of tellurite to induce phosphorylation of eIF2α, stress granules (SGs) assembly and their relationship with DNA damage in U2OS cells. We demonstrate that tellurite promotes the assembly of bona fide cytoplasmic SGs. Unexpectedly, tellurite also induces the assembly of nuclear SGs. Interestingly, we observed that the presence of tellurite-induced nuclear SGs correlates with γH2AX foci. However, although H2O2 also induce DNA damage, no nuclear SGs were observed. Our data show that tellurite promotes the assembly of cytoplasmic and nuclear SGs in response to oxidative stress and DNA damage, revealing a new aspect of cellular stress response mediated by the assembly of nuclear stress granules.

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