Kaushik Susmita, Cuervo Ana Maria
1] Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nat Cell Biol. 2015 Jun;17(6):759-70. doi: 10.1038/ncb3166. Epub 2015 May 11.
Chaperone-mediated autophagy (CMA) selectively degrades a subset of cytosolic proteins in lysosomes. A potent physiological activator of CMA is nutrient deprivation, a condition in which intracellular triglyceride stores or lipid droplets (LDs) also undergo hydrolysis (lipolysis) to generate free fatty acids for energetic purposes. Here we report that the LD-associated proteins perilipin 2 (PLIN2) and perilipin 3 (PLIN3) are CMA substrates and their degradation through CMA precedes lipolysis. In vivo studies revealed that CMA degradation of PLIN2 and PLIN3 was enhanced during starvation, concurrent with elevated levels of cytosolic adipose triglyceride lipase (ATGL) and macroautophagy proteins on LDs. CMA blockage both in cultured cells and mouse liver or expression of CMA-resistant PLINs leads to reduced association of ATGL and macrolipophagy-related proteins with LDs and the subsequent decrease in lipid oxidation and accumulation of LDs. We propose a role for CMA in LD biology and in the maintenance of lipid homeostasis.
伴侣介导的自噬（CMA）可选择性地降解溶酶体中的一部分胞质蛋白。CMA的一种强效生理激活剂是营养剥夺，在这种情况下，细胞内甘油三酯储存或脂滴（LDs）也会发生水解（脂解作用），以产生用于能量目的的游离脂肪酸。在此我们报告，与脂滴相关的蛋白围脂滴蛋白2（PLIN2）和围脂滴蛋白3（PLIN3）是CMA的底物，并且它们通过CMA的降解先于脂解作用。体内研究表明，在饥饿期间，PLIN2和PLIN3的CMA降解增强，同时脂滴上的胞质脂肪甘油三酯脂肪酶（ATGL）和巨自噬蛋白水平升高。在培养细胞和小鼠肝脏中阻断CMA或表达抗CMA的PLINs会导致ATGL和大脂自噬相关蛋白与脂滴的结合减少，随后脂质氧化减少和脂滴积累。我们提出CMA在脂滴生物学和脂质稳态维持中发挥作用。
