Kumar Ashutosh, Zhao Yonghui, Xie Litao, Chadda Rahul, Tranter John D, Mikami Ryan T, Abraham Nihil, Hong Juan, Feng Ethan, Rawnsley David R, Liu Haiyan, Henry Kayla M, Meyer Gretchen, Hu Meiqin, Xu Haoxing, Hinton Antentor, Grueter Chad E, Abel E Dale, Norris Andrew W, Diwan Abhinav, Sah Rajan
Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA.
Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA.
Sci Adv. 2025 Sep 26;11(39):eadt6366. doi: 10.1126/sciadv.adt6366.
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.
溶酶体整合合成代谢信号和营养感知以调节细胞内生长途径。富含亮氨酸重复序列8（LRRC8）通道复合物形成溶酶体阴离子通道，并调节PI3K-AKT-mTOR信号传导、骨骼肌分化、生长和全身葡萄糖代谢。在这里，我们确定了定位于分化肌管中一部分溶酶体的内源性LRRC8亚基。我们发现LRRC8A影响亮氨酸刺激的mTOR；溶酶体大小；数量；pH值；溶酶体蛋白LAMP2、P62和LC3B的表达；以及溶酶体功能。在肌管中突变LRRC8A溶酶体靶向双亮氨酸基序序列（LRRC8A-L706A；L707A）可重现LRRC8A基因敲除细胞中观察到的异常AKT信号传导以及溶酶体形态和pH值的改变。在体内，LRRC8A-L706A；L707A基因敲入小鼠表现出肥胖增加、葡萄糖耐量受损和胰岛素抵抗，这与骨骼肌PI3K-AKT-mTOR信号传导降低、葡萄糖摄取减少以及葡萄糖掺入糖原受损有关。这些数据揭示了溶酶体LRRC8介导的代谢信号功能，其调节溶酶体功能、全身葡萄糖稳态和胰岛素敏感性。
