IRE1? negatively regulates IRE1? signaling in response to endoplasmic reticulum stress.

ABSTRACT: IRE1? is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1? have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1? diminishes expression and inhibits signaling by the closely related stress sensor IRE1?. IRE1? can assemble with and inhibit IRE1? to suppress stress-induced XBP1 splicing, a key mediator of the unfolded protein response. In comparison to IRE1?, IRE1? has relatively weak XBP1 splicing activity, largely explained by a nonconserved amino acid in the kinase domain active site that impairs its phosphorylation and restricts oligomerization. This enables IRE1? to act as a dominant-negative suppressor of IRE1? and affect how barrier epithelial cells manage the response to stress at the host-environment interface.

SUBMITTER: Grey MJ 

PROVIDER: S-EPMC7041686 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature