Defective Lamtor5 Leads to Autoimmunity by Deregulating v‐ATPase and Lysosomal Acidification
0301 basic medicine
v‐ATPase
Vacuolar Proton-Translocating ATPases
0303 health sciences
lamtor5
Science
autoimmunity
Q
Autoimmunity
Mechanistic Target of Rapamycin Complex 1
Mice
Disease Models, Animal
lysosome
Leukocytes, Mononuclear
Animals
Humans
Lupus Erythematosus, Systemic
Female
Lysosomes
Research Articles
DOI:
10.1002/advs.202400446
Publication Date:
2024-04-19T11:10:29Z
AUTHORS (12)
ABSTRACT
AbstractDespite 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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (53)
CITATIONS (4)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....