# Mechanism of action for the epithelial-specific ER stress sensor IRE1β in regulating intestinal homeostasis and host defense

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $759,238

## Abstract

PROJECT SUMMARY
Our overarching goal is to understand how the epithelial-specific ER stress sensor IRE1b (ERN2) and its
ubiquitously expressed paralogue IRE1a (ERN1) contribute to intestinal homeostasis and host defense.
A notable adaptation of the ER unique to epithelial cells lining mucosal surfaces, especially in the gut, is
expression of the ER stress sensor IRE1b, a close paralogue of the major and most evolutionarily conserved ER
stress sensor IRE1a. We recently discovered, however, that IRE1b functions distinctly from IRE1a in enzymatic
activity, enabling it to act as a non-competitive inhibitor of IRE1a signaling in the ER stress response. Our new
and ongoing studies demonstrate in vivo that IRE1b operates critically in goblet cell differentiation and assembly
of the mucus barrier - with both activities dependent on the normal gut microbiota: gut microbes and their
products stimulate IRE1b expression, and IRE1b in turn affects the assembly, taxonomy, and functional output
of colonizing gut microbes.
These data frame our central hypothesis that IRE1b acts as an environmentally induced mediator of innate
epithelial host defense by affecting the ER stress response via IRE1a, and then goblet cell development,
mucus assembly, and host epithelial-microbe interactions that shape the structure and function of the colon.
In Aim 1, we will use recombinant proteins and biochemical and biophysical approaches to test how IRE1a and
IRE1b may be activated by gut lumenal factors, explain how IRE1b oligomerizes with IRE1a, and elucidate what
structural features and post-translational modifications modify this assembly, IRE1b signaling, and mechanisms
for IRE1b activation and suppression of IRE1a function.
In Aim 2, we will use wt and IRE1b-/- mice and colonoids prepared from these animals to determine how IRE1b
links the gut microbiota with epithelial stress and development responses and identify core microbial pathways
and metabolites that regulate IRE1b expression and perhaps function.
In Aim 3, we will explain how the lack of IRE1b attenuates recovery from acute infection with C. rodentium. We
found that IRE1b-/- mice have impaired assembly of the colonic mucus layer and dysbiosis - mimicking defects
in the colonic mucosa seen in humans with ulcerative colitis (UC). As modeled by Citrobacter rodentium, the
altered mucus layer in IRE1b-/- mice was associated with impaired recovery following normal clearance of the
pathogen. We will (i) test if the dysbiotic gut microbiota, or unresolved epithelial ER stress, or both, drive the
sustained inflammation following C. rodentium infection in IRE1b-/- mice; and (ii) determine if microbiota obtained
from humans with UC phenocopy these effects and fail to induce IRE1b, goblet cell development, or an effective
mucus barrier when reconstituted in germ-free wt IRE1b+/+ mice.
ER stress is implicated in the chronic inflammatory and other intestinal diseases. The outcomes of these studies
will be informative of the hos...

## Key facts

- **NIH application ID:** 10376830
- **Project number:** 5R01DK048106-29
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael J Grey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $759,238
- **Award type:** 5
- **Project period:** 1993-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376830

## Citation

> US National Institutes of Health, RePORTER application 10376830, Mechanism of action for the epithelial-specific ER stress sensor IRE1β in regulating intestinal homeostasis and host defense (5R01DK048106-29). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10376830. Licensed CC0.

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