Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy

• Type of Material: Article
• Authors: Wenming Li, Emory University; Jinqiu Zhu, Emory University; Juan Dou, Emory University; Hua She, Emory University; Kai Tao, The Fourth Military Medical University; Haidong Xu, Emory University; Qian Yang, The Fourth Military Medical University; Zixu Mao, Emory University
• Language: English
• Date: 2017-11-24
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-017-01609-x
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 8
• Start Page: 1763
• End Page: 1763
• Grant/Funding Information: This work was partially supported by grants from NIH (NS079858, AG023695, and NS095269 (Z. Mao)), Michael J. Fox Foundation (Z. Mao), and National Natural Science Foundation of China (No. 31371400 and 31671060 (Q.Yang)).
• Keywords: endoplasmic reticulum; lysosomes; chaperone-mediated autophagy
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology; Health Sciences, Epidemiology

Abstract

Endoplasmic reticulum (ER) and lysosomes coordinate a network of key cellular processes including unfolded protein response (UPR) and autophagy in response to stress. How ER stress is signaled to lysosomes remains elusive. Here we find that ER disturbance activates chaperone-mediated autophagy (CMA). ER stressors lead to a PERK-dependent activation and recruitment of MKK4 to lysosomes, activating p38 MAPK at lysosomes. Lysosomal p38 MAPK directly phosphorylates the CMA receptor LAMP2A at T211 and T213, which causes its membrane accumulation and active conformational change, activating CMA. Loss of ER stress-induced CMA activation sensitizes cells to ER stress-induced death. Neurotoxins associated with Parkinson's disease fully engages ER-p38 MAPK-CMA pathway in the mouse brain and uncoupling it results in a greater loss of SNc dopaminergic neurons. This work identifies the coupling of ER and CMA as a critical regulatory axis fundamental for physiological and pathological stress response.