Coupling of Stress in the ER to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1

TLDR

ER stress from misfolded proteins activates JNKs, and this pathway resembles the cell surface receptor–initiated JNK activation. IRE1’s cytoplasmic domain binds TRAF2, linking ER stress to JNK activation. IRE1 homologs activate JNK, and loss of IRE1α or inhibition of TRAF2 impairs this activation.

Abstract

Malfolded proteins in the endoplasmic reticulum (ER) induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs). Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1 α −/− fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. Dominant-negative TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the ER proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.