Higuchi-Sanabria Ryo, Shen Koning, Kelet Naame, Frankino Phillip A, Durieux Jenni, Bar-Ziv Raz, Sing Cierra N, Garcia Enrique J, Homentcovschi Stefan, Sanchez Melissa, Wu Rui, Tronnes Sarah U, Joe Larry, Webster Brant, Ahilon-Jeronimo Alex, Monshietehadi Samira, Dallarda Sofia, Pender Corinne, Pon Liza A, Zoncu Roberto, Dillin Andrew
Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720-3370, USA.
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Sci Adv. 2020 Jun 26;6(26):eaaz9805. doi: 10.1126/sciadv.aaz9805. eCollection 2020 Jun.
Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPR. Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1-dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.
最近的研究突出了这样一个事实，即溶酶体是代谢过程的关键信号枢纽，为合成代谢功能提供至关重要的基本组成部分。溶酶体功能如何影响其他细胞区室尚不完全清楚。在此，我们发现氨基酸赖氨酸和精氨酸的溶酶体再循环对于通过未折叠蛋白反应（UPR）进行适当的内质网（ER）质量控制至关重要。具体而言，赖氨酸和精氨酸氨基酸转运体LAAT-1的缺失导致对内质网中蛋白毒性应激的敏感性增加以及动物生理功能下降。我们发现这些依赖LAAT-1的效应与甘氨酸代谢和转运有关，并且甘氨酸转运体SKAT-1功能的丧失也会增加对内质网应激的敏感性。直接补充赖氨酸和精氨酸，或单独补充甘氨酸，可以改善在突变体中发现的内质网应激敏感性增加的情况。这些数据表明赖氨酸、精氨酸和甘氨酸的再循环在溶酶体与内质网之间的通讯中起着关键作用。
