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

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.

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

“…In fact, under some circumstances, ER stress-induced elevation of ATF4 protein levels can occur independently of PERK [30] and ER stress-mediated induction of CHOP can occur independently of ATF4 [41]. Moreover, PERK can exert cellular effects via other mechanisms than through ATF4 [30,38,[41][42][43][44], and ATF4 has many target genes other than CHOP [41,45]. Consequently, careful experimental study is required to determine the individual roles of PERK, ATF4, and CHOP in ER stress-induced regulation of cell death and DR5 expression.…”

A Chemical Genetics Screen Reveals Influence of p38 Mitogen-Activated Protein Kinase and Autophagy on Phagosome Development and Intracellular Replication of Brucella neotomae in Macrophages

“…Furthermore, p38 itself was found to phosphorylate LAMP-2A in lysosomes and thereby activate autophagic machinery (38). In addition, ER stress-induced autophagy induction was found to be a p38-dependent process (38)(39)(40). The JNK pathway was also found to stimulate autophagy (41) and may coordinately activate autophagy along with p38 in response to stress.…”

“…For example, in RAW macrophages, interferon gamma (IFN-␥)-induced autophagy was blocked by treatment with SB203850 and also, interestingly, by JAK inhibition, reminiscent of our JAK inhibitor screening hit, CYT397 (37). Furthermore, p38 itself was found to phosphorylate LAMP-2A in lysosomes and thereby activate autophagic machinery (38). In addition, ER stress-induced autophagy induction was found to be a p38-dependent process (38)(39)(40).…”

Peer Review #3 of "Endoplasmic reticulum stress and the protein degradation system in ophthalmic diseases (v0.1)"

“…In the process of microautophagy, the lysosomal membrane acts as a concave protuberance or membrane, allowing a small portion of the cytoplasmic volume to enter the lysosomal cavity, which degrades the substrate (Li et al 2012). Molecular CMA does not require vacuolar formation and is tightly regulated by chaperone heat shock cognate 71 kDa protein (Hsc70) and its receptor, and it is associated with the PERK pathway in ER stress (Li et al 2017b). Manuscript to be reviewed 2015).…”