# Essential role of the Ufm1 E3 ligase in intestinal homeostasis

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $342,000

## Abstract

Project Summary:
Intestinal homeostasis is crucial for normal intestinal functions, and its disruption may lead to the pathogenesis
of human diseases such as chronic inflammation and even cancer. Paneth cells play crucial roles in intestinal
barrier function and mucosal immunity. Recent studies have demonstrated that impaired function of Paneth
cells may lead to dysbiotic intestine and increased susceptibility to inflammatory bowel disease (IBD). The
Ufm1 (Ubiquitin-fold modifier 1) conjugation system is a novel ubiquitin-like system that consists of Ufm1-
sepcific E1 enzyme (Uba5), E2 enzyme (Ufc1) and a putative E3 enzyme (a protein complex containing Ufl1
and Ufbp1). Clinical and animal model studies implicate its potential involvement in many diseases such as
neurological disorders, ischemic injury and cancer, but its overall functions and underlying mechanisms remain
poorly understood. Genetic studies from others and us have recently demonstrated the essential role of this
system in embryonic development and hematopoiesis, but its role in other systems remains to be defined. Ufl1
and Ufbp1, the key components of Ufm1 E3 ligase, are present in multiple tissues and organs and highly
expressed in the intestine, yet their role in the gut is completely unknown. The observation of frequent gut
bleeding in Ufl1 and Ufbp1 knockout mice prompted us to generate IEC (intestinal epithelial cell)-specific
knockout mouse models of Ufl1 and Ufbp1. We found that IEC-specific ablation of either Ufl1 or Ufbp1 caused
nearly complete loss of Paneth cells and partial loss of goblet cells, resulting in increased susceptibility to
experimental colitis. Moreover, Ufbp1 ablation led to elevated ER (endoplasmic reticulum) stress, activation of
the Unfolded Protein Response (UPR) and apoptosis in IECs. We also observed dramatic increase of mRNAs
of secretory proteins such as lysozyme during the course of acute Ufbp1 ablation. We hypothesize that Ufbp1
and the ufmylation pathway plays a pivotal role in IRE1-mediated degradation of ER-associated mRNAs,
thereby coordinating protein synthesis and ER protein load and maintaining ER homeostasis of Paneth cells.
Ufbp1 deficiency impairs this degradation mechanism and leads to increased mRNAs and protein translation,
resulting in elevated ER stress and Paneth cell death. To test this hypothesis, we propose three specific aims.
Aim 1: To define Paneth cell-specific function of Ufbp1; Aim 2: To investigate the role of UPR in Paneth cell
apoptosis induced by Ufbp1 deficiency; and Aim 3: To elucidate the mechanism of Ufbp1 ablation-induced
disruption of ER homeostasis. The outcome of this project will provide critical insight into the physiological
function and working mechanism of this important protein modification system in maintaining intestinal
homeostasis., and have a significant impact on our understanding of Paneth cell biology, development of
novel therapeutic targets for inflammatory disease, and the physiological funct...

## Key facts

- **NIH application ID:** 9978762
- **Project number:** 5R01DK113409-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** HONGLIN LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978762

## Citation

> US National Institutes of Health, RePORTER application 9978762, Essential role of the Ufm1 E3 ligase in intestinal homeostasis (5R01DK113409-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9978762. Licensed CC0.

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