Evolution and function of the epithelial cell-specific ER stress sensor IRE1β

Abstract

Barrier epithelial cells lining the mucosal surfaces of the gastrointestinal and respiratory tracts interface directly with the environment. As such, these tissues are continuously challenged to maintain a healthy equilibrium between immunity and tolerance against environmental toxins, food components, and microbes. An extracellular mucus barrier, produced and secreted by the underlying epithelium plays a central role in this host defense response. Several dedicated molecules with a unique tissue-specific expression in mucosal epithelia govern mucosal homeostasis. Here, we review the biology of Inositol-requiring enzyme 1β (IRE1β), an ER-resident endonuclease and paralogue of the most evolutionarily conserved ER stress sensor IRE1α. IRE1β arose through gene duplication in early vertebrates and adopted functions unique from IRE1α which appear to underlie the basic development and physiology of mucosal tissues.

IRE1β does not affect mucus secretion during allergic asthma development in a house dust mite murine model

“…2 In line with its tissue-specific expression, IRE1β has been implicated in mucin production in both lung and gut epithelia. 2 As mucus overproduction is an important clinical feature in many asthma patients, 3 IRE1β may pose an attractive pharmacological treatment option. In ovalbumin (OVA)induced experimental asthma, IRE1β regulates mucin production through splicing of XBP1 4 ; however, its role in the more physiologically relevant house dust mite (HDM) model remains as yet unexplored.…”

“…based endonucleases that generate the transcription factor X-box binding protein 1 (XBP1)s through splicing of Xbp1 mRNA. 2 In line with its tissue-specific expression, IRE1β has been implicated in mucin production in both lung and gut epithelia. 2 As mucus overproduction is an important clinical feature in many asthma patients, 3 IRE1β may pose an attractive pharmacological treatment option.…”

“…Eva Cloots 1,2,3 Nincy Debeuf 1,4 Kim Deswarte 1,4 Farzaneh Fayazpour 1,2 Manon Vanheerswynghels 1,4 Caroline De Wolf 1,4 Evelien Van De Velde…”

ROS and Endoplasmic Reticulum Stress in Pulmonary Disease

“…COPD patients have more mucus cells in their respiratory tract, often secreting a lot of mucus. IRE1 β (inositol-requiring enzyme 1beta) of airway goblet cells plays an important role in mucin cell phenotype and secretion of mucin5AC and mucin5B ( Cloots et al, 2021 ). Michael found that in HEK293 cells models with purified protein, IRE1 α is closely related with IRE1 β diminishing expression and inhibiting signaling.…”

Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression

“…Metazoans have two IRE1 paralogues, IRE1α (referred to as IRE1 in this paper) and IRE1β. While IRE1α is ubiquitously expressed, IRE1β expression is restricted to gastrointestinal epithelium (Cloots et al , 2021 ). To date, IRE1 has been described to trans‐ autophosphorylate as a first step in the activation of its RNase modality, which initiates a nonconventional RNA‐splicing reaction and the production of the transcription factor known as spliced X box protein‐1 (XBP1s), which is one of the key drivers of the unfolded protein response (UPR) (Walter & Ron, 2011 ; Çimen et al , 2016a ; Robblee et al , 2016 ).…”