Talk abstracts

Talk on Friday 03:45-04:00pm submitted by Mithu Majumder

A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation

Mithu Majumder (Department of Nutrition, Case Western University School of Medicine, Cleveland, OH 44106. ), Charlie Huang (Department of Nutrition, Case Western University School of Medicine, Cleveland, OH 44106. ), Martin D. Snider (Department of Biochemistry, Case Western University School of Medicine, Cleveland, OH 44106. ), Anton A. Komar (Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, 44115.), Randal J. Kaufman (Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037), Dawid Krokowski and Maria Hatzoglou (Departments of Nutrition,Case Western University School of Medicine, Cleveland, OH 44106. )

Abstract:
The accumulation of unfolded proteins in the endoplasmic reticulum triggers transcriptional and translational reprogramming. This unfolded protein response (UPR) protects cells during transient stress and can lead to apoptosis during prolonged stress. Two key mediators of the UPR are PERK, which phosphorylates the translation initiation factor eIF2α, resulting in decreased protein synthesis, and IRE1α, which initiates cytoplasmic splicing of the mRNA encoding the transcription factor XBP1. XBP1 induces transcription of genes involved in protein quality control. This report describes a cross-talk between these two pathways: phosphorylation of eIF2α was required for maximal induction of spliced XBP1 (XBP1s) protein levels via a mechanism that involved stabilization of XBP1s mRNA. Using MEFs deficient in UPR signaling pathways, we demonstrate that stress-induced stabilization of XBP1s mRNA requires cytoplasmic splicing of the mRNA and inhibition of its translation. Because XBP1s protein promotes transcription of its own gene, the UPR induced mRNA stabilization is part of a positive feedback loop that induces XBP1s protein accumulation and transcription of target genes during stress. We propose a model where eIF2α phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress-response transcription program and the ER’s capacity to handle protein folding during stress.

Keywords: ER stress, mRNA stability