Lamtor5 maintains immune homeostasis by regulating lysosomal activity via v-ATPase and mTOR signaling
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ABSTRACT:
PROVIDER: PRJNA942946 | ENA |
REPOSITORIES: ENA
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Project description:Despite accumulating evidences linking defective lysosome function with autoimmune diseases, how the catabolic machinery is regulated for immune homeostasis remains largely unknown. Lamtor5 is a subunit of the Ragulator mediating mTORC1 activation in response to amino acids, but its action mode and physiological role are yet to be addressed. Here we unexpectedly found that myeloid Lamtor5 ablating mice developed spontaneous inflammation and systemic lupus erythematosus (SLE)-like manifestation. Loss of Lamtor5 in macrophages caused impaired vacuolar H⁺-ATPase (v-ATPase) activity, lysosome de-acidification, and aberrant mTORC1 activation, correlating with undesirable inflammatory responses. Mechanistically, we showed that Lamtor5 physically associated with ATP6V1A, an essential subunit of v-ATPase, and promoted the V0/V1 holoenzyme assembly for lysosome acidification. Notably, binding of Lamtor5 to v-ATPase substantially affected lysosomal tethering of Rag GTPase and weakened its interaction with mTORC1 for activation. Importantly, defective Lamtor5 expression, along with impaired lysosomal function and hyperactivation of mTORC1, was corroborated in peripheral blood mononuclear cells (PBMCs) of SLE patients and correlated with disease severity. Overall, our findings establish Lamtor5 as a new lysosome regulator, and elucidate an unappreciated mechanism that coordinates catabolic and anabolic pathways to bolster immune homeostasis preventing autoimmunity.
2024-03-03 | GSE227039 | GEO
Project description:TFEB-vacuolar ATPase signaling regulates lysosomal activity and immune response in tauopathy
| PRJNA905364 | ENA
Project description:Tay-Sachs disease (TSD) is a inherited lysosomal storage disease resulting from mutations in the α-subunits of the lysosomal enzyme, β-hexosaminidase A, and leads to excessive accumulation of GM2 ganglioside. This disease can be presented in infantil, juvenil and adult forms with rapid, progressive neurodegeneration. Although the link between mTOR and autophagy in Taysachs diseases has not been previously examined, it is reasonably to infer that reduced activity of HexA and the consequent intracellular accumulation of undegraded ganglyosides could lead accumulation of lysosomes, other substrates or dysfunctional organelles, similar to other defects detected in other LSD. In the present study, we show that skin fibroblasts derived from PLS patients presented increased p62/SQSTM1 expression levels and autophagosome accumulation suggesting an impaired autophagic flux.
2021-09-30 | GSE184906 | GEO
Project description:To investigate the putative differential effect of chloride transport on lysosomal ion homeostasis,we generated an ODE mathematical model for this system. Our mathematical model builds upon a previously published model for lysosomal homeostasis (Grabe et al. 2001 J. Gen. Physiol, Ishida et al. 2013 J. Gen. Physiol), and further includes the (de)activation kinetics of the ClC-7 antiporter and Ca2+ uptake/release mechanisms. Our new model tracks the total number of ions within the lysosomal lumen over time. It considers different types of lysosomal ion channels and exchangers and two possible lysosomal Ca2+ transporters. The variation in the total number of each ion within the lysosome is described by an ordinary differential equation (ODE), and the rate of change is determined by the flux of the corresponding ion across the lysosomal membrane. The model considers different elements affecting lysosomal ion homeostasis, among which are: (i) the V-ATPase pump, (ii) a proton leak, (iii) the luminal proton buffering capacity, (iv) ClC-7 chloride/proton exchanger, (v) Ca2+ /proton exchanger (CAX), (vi) passive channels for K+ , Na+ , and Ca2+ , and (vii) Donnan particles, which are negatively charged particles or molecules trapped in the lysosomal lumen. It allows for the simulation of different scenarios mimicking the differential transport of chloride, its impact on Ca2+ uptake and release and ultimately on lysosomal homeostasis. We provide a Supplementary Information file (Astaburuaga et al. Cells 2019) with the full description of the mathematical model. The equations written in purple were newly developed, the other elements were retrieved from a previous mathematical model as indicated above.
2019-10-22 | MODEL1910220001 | BioModels
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
Project description:Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of membrane proteins from limiting membranes of late endosomes. Recent studies revealed that yeast ESCRT proteins also sort for degradation, ubiquitinated proteins from vacuolar membrane. However, whether mammalian ESCRTs perform similar function at lysosomes remained unknown. Here, we studied the involvement of mammalian ESCRT-I in maintaining lysosomal membrane homeostasis and its implication in lysosome-related signaling. We show that ESCRT-I restricts the size of lysosomes and promotes degradation of lysosomal Ca2+ channel, MCOLN1 protein. ESCRT-I depletion induced transcriptional response related to MiT-TFE signaling and cholesterol biosynthesis, pointing to lysosomal dysfunction. The lack of ESCRT-I promoted abnormal cholesterol accumulation on lysosomes and activated TFEB/TFE3 transcription factors in Ca2+-MCOLN1-dependent, but lipid-independent manner. Hence, our study provides evidence that ESCRT-I maintains lysosomal homeostasis and elucidates MiT-TFE regulatory mechanism activated in response to ESCRT-I deprivation
2022-03-28 | GSE178665 | GEO
Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.
2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress
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
| MSV000088152 | MassIVE
Project description:Presenilin 1 (PS1) deletion or Alzheimer's disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca(2+) efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca(2+). In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca(2+) homeostasis, but correcting lysosomal Ca(2+) deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca(2+) homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.
| S-EPMC4558203 | biostudies-literature
Project description:Glioblastoma (GBM) is the most aggressive and common malignant brain tumor in adults. GBMs are characterized by high intratumor heterogeneity and by the presence of the cancer stem cell niche. The vacuolar ATPase (V-ATPase) is a multisubunit proton pump that plays a role in multiple processes in eukaryotic cells. Altered V-ATPase activity is associated with several human diseases and in cancer may play relevant role due the acidification of cellular organelles, such as, endosomes and lysosomes. We identified overexpression of the V-ATPase V1G1 subunit in GBM derived neurospheres (NS), a cell subpopulation enriched in cancer stem cells. Interestingly GBM NS secrete different types of vesicles, including large oncosomes (LO) thereby influencing their microenvironment. Herein, we assessed the transcriptome of non-sphere forming glioma cells (n=2 pairs) cocultured with LO or empty media (mock) by microarray to identify pathways associated with the LO-induced reprogramming ability. Gene set enrichment analysis (GSEA) revealed that LO-supplemented cultures activated a number of cancer-related pathways, including those involved in glioma V-ATPase-related signaling (Notch, mTOR, and lysosomal transport), as well as cell proliferation and cell transcription programs.
2019-05-10 | GSE120793 | GEO