# The UFM1 Conjugation System: A Master Regulator of Cellular Stress Surveillance in Human Disease

## TL;DR

The UFM1 conjugation system helps cells handle stress and is linked to diseases when it malfunctions.

## Contribution

This review highlights the UFM1 conjugation system as a novel regulator of cellular stress and a potential therapeutic target.

## Key findings

- UFMylation regulates endoplasmic reticulum stress, DNA repair, and autophagy.
- Dysregulation of UFM1 contributes to inflammatory diseases and cancer.
- UFM1 conjugation system components include UBA5, UFC1, UFL1, and others.

## Abstract

The cellular stress response plays a critical role in maintaining cell homeostasis when cells are exposed to various internal and external stressors that threaten their survival. UFMylation, mediated by the UFM1 conjugation system, a newly identified ubiquitin-like modification pathway, is essential for coordinating these stress responses, including endoplasmic reticulum stress, DNA damage repair, and autophagy, etc. Dysregulation of the UFM1 conjugation system disrupts substrate protein stability and stress signaling fidelity, contributing to the development of diverse human diseases. Our review summarizes recent, newly found evidence of how UFM1 conjugation system-mediated UFMylation governs cellular stress response surveillance and highlights its potential as a promising therapeutic target in various stress-associated inflammation disorders and cancers.

Post-translational modification (PTM) encompasses diverse modifications, including phosphorylation, methylation, ubiquitin-like modifications (UBLs), and so on, which profoundly influence cellular functions. UFMylation is a recently identified ubiquitin-like modification, which is mediated by the Ubiquitin-like Ubiquitin Fold Modifier 1 (UFM1) conjugation system. The UFM1 conjugation system comprises UFM1, Ubiquitin-like protein activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1), UFM1-specific ligase 1 (UFL1), UFM1-specific protease 1 (UFSP1), UFM1-specific protease 2 (UFSP2), UFM1-binding protein 1 (UFBP1), and CDK5 regulatory subunit-associated protein 3 (CDK5RAP3). Accumulating research has demonstrated that the UFM1 conjugation system regulates various cellular stress responses, including endoplasmic reticulum (ER) stress, protein trafficking, DNA damage repair, and autophagy. Additionally, abnormal stress adaptations of the UFM1 conjugation system contribute to the pathophysiological complications of inflammatory diseases and cancer, underscoring its significance as a key regulatory node in human health and disease. Therefore, this review provides a comprehensive exploration of the structural characteristics of UFM1 conjugation system members and the mechanistic roles of UFMylation by UFM1 conjugation system-mediated diseases related to cellular stress responses, which will not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for UFM1 conjugation system-related diseases.