Chronic mTOR activity impaires lysosome maturation in lupus

Abstract

Abstract Multiple genetic and environmental factors activate lymphocytes and myeloid cells to promote systemic lupus erythematosus (SLE). This complexity has made it difficult to define underlying mechanisms. We previously demonstrated that hematopoietic cells from lupus-prone mice accumulate nuclear antigens on their cell surface due to an inability to mature the lysosome. On myeloid cells, the accumulation of nuclear antigens reflects IgG-immune complexes (IgG-ICs) bound to FcγRs. Further, lupus-prone mice lacking FcγRI fail to develop myeloid and lymphoid-associated pathologies suggesting a critical role for FcγRI in SLE. How FcγRI signaling influences lysosomal maturation is unclear. Herein, we show that lysosome acidification, a key step in the maturation process, relies on the strict regulation of mTORC2, activation of caspase-1, and cleavage of Rab39a. In macrophages from MRL/lpr mice, we find that chronic mTORC2 activation disrupts lysosomal maturation by inducing constitutive phosphorylation of cofilin. This prevents the association of cofilin with phagosomes containing IgG-ICs. As a result, inflammasome-independent activation of caspase-1 in proximity to the phagosome does not occur. Consequently, Rab39a remains intact on the phagosomal membrane, and the lysosome does not acidity. These findings reveal unique roles for mTORC2, cofilin, and pyroptototic caspases critical to an unappreciated signaling pathway promoting lysosome acidification. Further, this signaling cascade becomes disrupted in SLE, preventing the lysosome-mediated degradation of apoptotic debris upstream of multiple lupus-associated pathologies.