Protein Misfolding Induces Hypoxic Preconditioning via a Subset of the Unfolded Protein Response Machinery

• DOI: 10.1128/mcb.00922-10
• Publication Date: 2010-08-24T02:28:57Z
• Authors: Xianrong R. Mao; C. Michael Crowder
• Keywords: Integrated stress response; Chaperone (clinical); Proteostasis; Hypoxia

Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein pathway (UPR) has been known for some time to respond regulate sensitivity; however, the role of UPR, if any, HP essentially unexplored. We have shown previously that sublethal exposure nematode Caenorhabditis elegans induces chaperone component UPR (L. L. Anderson, X. Mao, B. A. Scott, C. M. Crowder, Science 323:630-633, 2009). Here, we show pharmacological induction misfolded proteins is itself sufficient stimulate delayed protective injury requires IRE-1, XBP-1, ATF-6. also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which suppress translation an adaptive transcriptional under conditions activation amino acid deprivation, was HP. phosphorylation factor eIF2α, established mechanism GCN-2-mediated translational suppression, necessary These data suggest model where hypoxia-induced trigger along with GCN-2 controls essential