Defective Lamtor5 Leads to Autoimmunity by Deregulating v-ATPase and Lysosomal Acidification

Despite accumulating evidence linking defective lysosome function with autoimmune diseases, how the catabolic machinery is regulated to maintain immune homeostasis remains unknown. 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-like 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+-ATPase (v-ATPase), and promoted the V0/V1 holoenzyme assembly to facilitate lysosome acidification. The binding of Lamtor5 to v-ATPase 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-ATPase activity, lysosome function, and mTOR pathway. The findings provide a potential therapeutic target for SLE and/or other autoimmune diseases. In this article, it is demonstrated that late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (Lamtor5) is physically associated with vacuolar H+-ATPase (v-ATPase) subunit ATP6V1A to promote lysosomal acidification, and simultaneously affected the Rag GTPase/mTORC1 interaction at lysosomes. This study established Lamtor5 as a critical regulator for immune homeostasis via regulating lysosomal v-ATPase and mTORC1 pathway, providing a novel insight into the pathogenesis of autoimmune diseases. image