Autophagy hub-protein p62 orchestrates oxidative, endoplasmic reticulum stress, and inflammatory responses...

Autophagy has crucial roles for ischemia/reperfusion (I/R) injury. To define the role of the autophagy hub protein p62/SQSTM1 in I/R injury, we conducted gain-of-function and loss-of-function experiments in a set of cell types, including two neuron-like cell lines, primary neurons, brain endothelial and astroglial-like cells, which we combined with mouse ischemic stroke studies. p62 levels post-I/R increased alongside intracellular ROS changes. p62 overexpression increased and p62 knockdown or pharmacological deactivation reduced I/R injury. Autophagic flux was p62-dependent, but oxygen-independent. Using p62 domain deletion mutants we identified p62's ZZ domain as key factor mediating autophagy and cell death. Death-promoting effects of p62 involved elevated ROS burden. At the same time, p62 activated a broad network of cytoprotective responses, which included NRF2-associated antioxidant signaling and inhibition of the pro-inflammatory NFκB pathway, which were bidirectionally linked with p62, and downregulation of the ER stress sensor BiP/GRP78 with consecutive activation of the UPR PERK branch. Our study establishes p62 as a master regulator of I/R injury, which offers itself as target for stroke therapies.