通过对溶酶体蛋白质组的生物信息学分析，研究人员确定了LYsosomal CHOlesterol Signaling（LYCHOS，以前被注释为G-蛋白偶联受体155），这是一种多域跨膜蛋白，能够使胆固醇依赖性地激活核心生长调节因子——蛋白激酶mTORC1（mechanistic Target of Rapamycin Complex 1）。胆固醇与LYCHOS的N端渗透酶样区域结合，突变该部位会损害mTORC1的激活。在高胆固醇浓度下，LYCHOS通过一个保守的面向细胞质的环与GATOR1复合物结合，GATOR1是Rag鸟苷三磷酸酶的GTP酶激活蛋白。通过封存GATOR1，LYCHOS促进胆固醇和Rag依赖的mTORC1被招募到溶酶体。因此，LYCHOS在溶酶体感知胆固醇的途径中发挥作用，并将胆固醇浓度与mTORC1依赖的合成代谢信号联系起来。
据了解，溶酶体在感受到包括胆固醇在内的基本营养物质后协调细胞的代谢和生长。
附：英文原文
Title: Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1
Author: Hijai R. Shin, Y. Rose Citron, Lei Wang, Laura Tribouillard, Claire S. Goul, Robin Stipp, Yusuke Sugasawa, Aakriti Jain, Nolwenn Samson, Chun-Yan Lim, Oliver B. Davis, David Castaneda-Carpio, Mingxing Qian, Daniel K. Nomura, Rushika M. Perera, Eunyong Park, Douglas F. Covey, Mathieu Laplante, Alex S. Evers, Roberto Zoncu
Issue&Volume: 2022-08-25
Abstract: Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified LYsosomal CHOlesterol Signaling (LYCHOS, previously annotated as G-protein coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1). Cholesterol bound to the N-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a GTPase-activating protein for the Rag guanosine triphosphatases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing, and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
DOI: abg6621
Source: https://www.science.org/doi/10.1126/science.abg6621