Unfolded protein response in brain ischemia: A timely update

Abstract

Folding and processing newly synthesized proteins are vital functions of the endoplasmic reticulum that are sensitive to a variety of stress conditions. The unfolded protein response is activated to restore endoplasmic reticulum function impaired by stress. While we know that brain ischemia impairs endoplasmic reticulum function, the role of unfolded protein response activation in post-ischemic recovery of neurologic function is only beginning to emerge. Here, we summarize what is known about endoplasmic reticulum stress and unfolded protein response in brain ischemia and discuss recent findings from myocardial ischemia studies that could help to advance research on endoplasmic reticulum stress and unfolded protein response in brain ischemia.

Keywords: Brain ischemia; endoplasmic reticulum; myocardial ischemia; stroke; unfolded protein response.

Figure 1.

Scheme of the unfolded protein response (UPR). UPR has three response branches controlled by stress sensor proteins in the ER membrane, the ATF6, the inositol-requiring enzyme-1 (IRE1), and the protein kinase RNA-like ER kinase (PERK). Activated ATF6 translocates to the Golgi where it is cleaved by proteases to the short form (sATF6) that translocates to the nucleus and activates expression of sATF6 target genes coding for ER chaperons, and proteins involved in ER-associated degradation (ERAD) and autophagy. ER stress turns IRE1 into an endonuclease that cleaves X-box binding protein-1 (Xbp1) mRNA. IRE1-induced splicing of Xbp1 mRNA triggers a frame-shift of the coding region, and formation of a new 54-kDa protein, XBP1s. XBP1s is a transcription factor that regulates expression of genes coding for ER chaperones, proteins involved in ERAD and in the hexosamine biosynthetic pathway that activates O-linked β-N-acetylglucosamine modification of proteins (O-GlcNAcylation). Activated PERK is turned into a kinase that phosphorylates eIF2α and thereby blocks the initiation process of translation. This promotes translation of Atf4 mRNA into the ATF4 protein, a transcription factor that activates expression of genes coding for pro-apoptosis protein including CHOP.