Liang X, Wei SQ, Lee SJ, Fung JK, Zhang M, Tanaka A, Choi AM, Jin Y

Lung epithelial cell death is a prominent feature of hyperoxic lung injury and has been considered to be a very important underlying mechanism of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Here we report a novel mechanism involved in the epithelial cytoprotection and homeostasis after oxidative stress. ...

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p62 (sequestosome 1 SQSTM1) is a ubiquitously expressed cellular protein. It interacts with ubiquitinated proteins and autophagic marker light chain 3b (LC3b), thus mediates the degradation of selective targets. In this study, we explored the role of p62 in mitochondria mediated cell death after hyperoxia. Lung alveolar epithelial cells have abundant p62 expression and the p62 level is up-regulated by oxidative stress at both protein and mRNA level. p62 / LC3b complex interacts with Fas and truncated BID (tBID) physically. These interactions abruptly diminish after hyperoxia. Deletion of p62 robustly increases tBID and cleaved caspase 3, implicating an anti-apoptotic effect. This anti-apoptotic effect of p62 is further confirmed by measuring caspase activities, cleaved PARP and cell viability. Deletion of the p62 PBI domain or UBA domain both lead to elevated t-BID, cleaved caspase 3 and significantly more cell death after hyperoxia. Additionally, p62 trafficks in an opposite direction with LC3b after hyperoxia, leading to the dissociation of p62/cav-1/LC3b/BID complex. Subsequently, LC3b mediated lysosomal degradation of tBID is eliminated. Taken together, our data suggest that p62 /LC3b complex regulates lung alveolar epithelial cell homeostasis and cytoprotection after hyperoxia.

Date: Jan. 18, 2013

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