Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism

Authors:

Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D. Tranter, Ryan T. Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R. Rawnsley, Haiyan Liu, Kayla M. Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton Jr., Chad E. Grueter, E. Dale Abel, Andrew W. Norris, Abhinav Diwan, Rajan Sah

Keywords:

Lysosome; LRRC8; leucine-rich repeat–containing 8; metabolic signaling

Abstract:

The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat–containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.

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