Fortilin binds IRE1α and prevents ER stress from signaling apoptotic cell death

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

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9 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 languageEnglish (US)
Article number41467
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Pinkaew, D., Chattopadhyay, A., King, M. D., Chunhacha, P., Liu, Z., Stevenson-Lerner, H., Chen, Y., Sinthujaroen, P., McDougal, O. M., & Fujise, K. (2017). Fortilin binds IRE1α and prevents ER stress from signaling apoptotic cell death. Nature Communications, 8(1), [41467]. https://doi.org/10.1038/s41467-017-00029-1