A Molecular Mechanism for Turning Off IRE1? Signaling during Endoplasmic Reticulum Stress.

ABSTRACT: Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1? endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress, thereby attenuating IRE1?. Although sustained activation of IRE1? is linked to human diseases, it is not clear how IRE1? is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1?/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1?. This leads to inhibition of higher-order oligomerization and attenuation of IRE1? RNase activity during prolonged ER stress. In Sec63-deficient cells, IRE1? remains activated for a long period of time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1? with Sec63/BiP to regulate the dynamics of IRE1? signaling in cells.

SUBMITTER: Li X 

PROVIDER: S-EPMC7809255 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature