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

Wenming Li,Zixu Mao,Juan Dou,Hua She,Jinqiu Zhu,Haidong Xu,Kai Tao,Qian Yang

doi:10.1038/s41467-017-01609-x

Wenming Li, Zixu Mao + Show 6 more

Open Access

https://doi.org/10.1038/s41467-017-01609-x

Copy DOI

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.

Highlights

Endoplasmic reticulum (ER) and lysosomes coordinate a network of key cellular processes including unfolded protein response (UPR) and autophagy in response to stress
ER stress activates chaperone-mediated autophagy (CMA) by increasing CMA receptor lysosome-associated membrane protein 2 A (LAMP2A). Because both UPR and CMA are involved in disposing proteins upon stress, we investigated the possibility that these two key protein quality control processes may be functionally related
Our studies have revealed that ER and lysosomes, the two key cellular stress organelles, are functionally coupled via p38 MAPK, the most critical stress signal transducer[21, 33, 34], via a process that we have termed ERICA

Summary

Introduction

Endoplasmic reticulum (ER) and lysosomes coordinate a network of key cellular processes including unfolded protein response (UPR) and autophagy in response to stress. Chaperone-mediated autophagy (CMA) selectively degrades individual cytosolic proteins[5, 6] This process does not require the formation of vacuole and is tightly controlled by two key CMA regulators, chaperone Hsc[70] and the receptor, lysosome-associated membrane protein 2 A (LAMP2A). The activated lysosomal p38 MAPK directly phosphorylates LAMP2A, causing its accumulation and oligomerization on the lysosomal membrane and activating CMA. We term this coupling ERICA for ER stress-induced CMA.

Methods

Results

Conclusion