Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Li, Wenming; Zhu, Jinqiu; Dou, Juan; She, Hua; Tao, Kai; Xu, Haidong; Yang, Qian; Mao, Zixu
• Is Part Of: Nature communications. Volume 8:Issue 1(2017)
• Page Start: 1
• Page End: 14
• Publication Date: 2017-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-017-01609-x
• Languages: English
• ISSNs: 2041-1723

Abstract

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. The endoplasmic reticulum (ER) and lysosome are central to cellular stress responses, but it is unclear how ER stress is signaled to lysosomes. Here the authors show that ER stress activates chaperone-mediated autophagy (CMA) via direct phosphorylation of the CMA receptor LAMP2A by the lysosomal p38 MAPK.