Lamtor5 maintains immune homeostasis by regulating lysosomal activity via v-ATPase and mTOR signaling

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.