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Late endosomal\/lysosomal adaptor, MAPK and mTOR activator 5 (Lamtor5) is a subunit of the Ragulator mediating mechanistic target of rapamycin complex 1 (mTORC1) activation in response to amino acids, but its action mode and physiological role are still unclear. Here it is demonstrated that Lamtor5 level is markedly decreased in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE). In parallel, the mice with myeloid Lamtor5 ablation developed SLE\u2010like manifestation. Impaired lysosomal function and aberrant activation of mTORC1 are evidenced in Lamtor5 deficient macrophages and PBMCs of SLE patients, accompanied by blunted autolysosomal pathway and undesirable inflammatory responses. Mechanistically, it is shown that Lamtor5 is physically associated with ATP6V1A, an essential subunit of vacuolar H\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase\u00a0(v\u2010ATPase), and promoted the V0\/V1 holoenzyme assembly to facilitate lysosome acidification. The binding of Lamtor5 to v\u2010ATPase affected the lysosomal tethering of Rag GTPase and weakened its interaction with mTORC1 for activation. Overall, Lamtor5 is identified as a critical factor for immune homeostasis by intergrading v\u2010ATPase activity, lysosome function, and mTOR pathway. The findings provide a potential therapeutic target for SLE and\/or other autoimmune diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202400446","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T07:10:29Z","timestamp":1713510629000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Defective Lamtor5 Leads to Autoimmunity by Deregulating v\u2010ATPase and Lysosomal Acidification"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-5758","authenticated-orcid":false,"given":"Wei","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Medicine Nanjing University of Chinese Medicine  Nanjing 210046 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Sha","sequence":"additional","affiliation":[{"name":"School of Medicine Nanjing University of Chinese Medicine  Nanjing 210046 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