Fortilin Binds IRE1α and Prevents ER Stress from Signaling Apoptotic Cell Death

Matthew D. King, Owen M. McDougal, Decha Pinkaew, Abhijnan Chattopadhyay, Preedakorn Chunhacha, Zhihe Liu, Heather L. Stevenson, Yanjie Chen, Patuma Sinthujaroen, Ken Fujise

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The endoplasmic reticulum, the cytoplasmic organelle that matures a massive amount of nascent secretory polypeptides, is particularly sensitive to stress. Endoplasmic reticulum stress causes unfolded proteins to populate the organelle, eliciting the unfolded protein response. During the unfolded protein response, GRP78—an endoplasmic reticulum master stress regulator—detaches from three endoplasmic reticulum stress sensors (IRE1α, PERK, and ATF6) and allows them to activate the apoptotic signaling pathway. Fortilin, a pro-survival molecule, is known to inhibit apoptosis by binding and inhibiting p53, but its role in endoplasmic reticulum stress-induced apoptosis remains unknown. Here, we report that fortilin directly interacts with the cytoplasmic domain of IRE1α, inhibits both kinase and endoribonuclease (RNase) activities of the stress sensor, and protects cells against apoptotic cell death at both cellular and whole animal levels. Our data support a role of fortilin in the unfolded protein response and its potential participation in human diseases caused by unfolded protein response.

Original languageAmerican English
Article number18
JournalChemistry and Biochemistry Faculty Publications and Presentations
Volume8
Issue number1
DOIs
StatePublished - 1 Jan 2017

EGS Disciplines

  • Chemistry

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