Talk abstracts

Talk on Friday 03:25-03:40pm submitted by Mithu Majumder

eIF2α phosphorylation dependent regulation of XBP1 mRNA turnover amplifies the UPR signaling during ER stress.

Mithu Majumder (Department of Nutrition, Case Western Reserve University.), Dawid Krokowski (Department of Nutrition, Case Western Reserve University.), Charlie Huang (Department of Nutrition, Case Western Reserve University.), Chuanping Wang (Department of Nutrition, Case Western Reserve University.), Maria Hatzoglou (Department of Nutrition, Case Western Reserve University.)

Abstract:
The accumulation of unfolded proteins in the endoplasmic reticulum triggers a stress response program that protects the cells early in the unfolded protein response (UPR) and can lead to apoptosis during prolonged stress. Upon the UPR, ER associated signaling pathways are activated. Early in the stress response, activation of the ER trans-membrane protein PERK causes increased phosphorylation of eIF2α, resulting in a global decrease of protein synthesis and increased synthesis of the transcription factor ATF4 which promotes expression of stress response genes. Later in the response, dephosphorylation of eIF2α allows translation of the transcribed stress response mRNAs. Early in the response, activation of the ER-transmembrane protein, IRE1α causes cytoplasmic splicing of a 26 nt intron from the ER-associated unspliced XBP1 mRNA. This splicing generates the active XBP1 transcription factor that induces the expression of genes involved in protein folding and degradation. The current view is that these two pathways are activated independently during the UPR. We show here that phosphorylation of eIF2α is required for maximal induction of the active XBP1 levels via a mechanism that involves stabilization of the spliced XBP1 mRNA. Using cells deficient for eIF2α phosphorylation, we show that splicing of the XBP1 mRNA is independent of eIF2α phosphorylation, but enhanced stabilization of the spliced mRNA requires global inhibition of protein synthesis (caused by eIF2α phosphorylation) which induces disassembly of ribosomes. We propose a model where early in the ER stress response, the unspliced XBP1 mRNA is spliced, generating a translationally repressed mRNA at a time when global protein synthesis is inhibited. Stabilization of the spliced mRNA allows its accumulation followed by translation during the subsequent translational recovery. We conclude that eIF2α-phosphorylation-mediated control of mRNA turnover amplifies the signals that promote the ER’s capacity to handle protein folding during stress.

Keywords: XBP1, mRNA stability