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

Wenming Li, Jinqiu Zhu, Juan Dou, Hua She, Kai Tao, Haidong Xu, Qian Yang () and Zixu Mao ()
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Wenming Li: Emory University School of Medicine
Jinqiu Zhu: Emory University School of Medicine
Juan Dou: Emory University School of Medicine
Hua She: Emory University School of Medicine
Kai Tao: The Fourth Military Medical University
Haidong Xu: Emory University School of Medicine
Qian Yang: The Fourth Military Medical University
Zixu Mao: Emory University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

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.

Date: 2017
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DOI: 10.1038/s41467-017-01609-x

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