Essential role of the Ufm1 E3 ligase in intestinal homeostasis

Ufm1 E3 连接酶在肠道稳态中的重要作用

基本信息

批准号：
9978762
负责人：
HONGLIN LI
金额：
$ 34.2万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978762
关键词：
Ablation Acute Animal Model Apoptosis Apoptotic Cell Death Cell Survival Cell physiology Cells Cellular biology Chronic Clinical Colitis Defensins Development Disease Embryonic Development Endoplasmic Reticulum Enzymes Epithelial Cells Estrogen receptor positive Genetic Models Genetic study Goals Goblet Cells Hematopoiesis Hemorrhage Homeostasis Impairment Inflammation Inflammatory Inflammatory Bowel Diseases Intestines Knockout Mice Lead Malignant Neoplasms Mediating Messenger RNA Mucosal Immunity Muramidase Organ Outcome Paneth Cells Pathogenesis Pathway interactions Physiological Play Post-Translational Protein Processing Predisposition Protein Biosynthesis Proteins Role Signal Pathway Signal Transduction Study models System Testing Tissues Transgenic Mice Translations Ubiquitin Work base dysbiosis endoplasmic reticulum stress human disease inhibitor/antagonist insight intestinal barrier intestinal epithelium intestinal homeostasis ischemic injury mRNA Transcript Degradation mouse model nervous system disorder new therapeutic target novel protein complex response secretory protein ubiquitin-protein ligase

项目摘要

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 function of the ufmylation pathway and its interplay with UPR.

项目摘要：肠稳态对于正常肠道功能至关重要，其破坏可能导致发病机理人类疾病，例如慢性炎症甚至癌症。 Paneth细胞在肠道中起着至关重要的作用屏障功能和粘膜免疫。最近的研究表明，Paneth的功能受损细胞可能导致失调肠，并增加对炎症性肠病（IBD）的敏感性。这 UFM1（泛素 - 折射剂1）共轭系统是一种新型的泛素样系统，由UFM1-组成 Sepcific E1酶（UBA5），E2酶（UFC1）和推定的E3酶（含有UFL1的蛋白质复合物和UFBP1）。临床和动物模型研究暗示了其潜在参与许多疾病，例如神经系统疾病，缺血性损伤和癌症，但其总体功能和潜在机制仍然存在理解不佳。来自他人和美国的遗传研究最近证明了这一点的重要作用胚胎发育和造血的系统，但其在其他系统中的作用仍有待定义。 UFL1 UFBP1是UFM1 E3连接酶的关键成分，存在于多个组织和器官中，高度在肠道中表达，但它们在肠道中的作用是完全未知的。观察频繁的肠道 UFL1和UFBP1敲除小鼠的出血促使我们生成IEC（肠上皮细胞） - 特异性 UFL1和UFBP1的敲除鼠标模型。我们发现UFL1或UFBP1的IEC特异性消融几乎完全失去了paneth细胞和杯状细胞的部分损失，从而增加了对实验性结肠炎。此外，UFBP1消融导致ER升高（内质网）应力，激活 IEC中展开的蛋白质反应（UPR）和凋亡。我们还观察到mRNA的显着增加急性UFBP1消融过程中的分泌蛋白，例如溶菌酶。我们假设UFBP1 ufmylation途径在IRE1介导的ER相关mRNA的降解中起关键作用，从而协调蛋白质合成和ER蛋白载荷，并维持Paneth细胞的ER稳态。 UFBP1缺乏症会损害这种降解机制，并导致mRNA和蛋白质翻译增加，导致ER应力升高和Paneth细胞死亡。为了检验这一假设，我们提出了三个具体目标。 AIM 1：定义UFBP1的Paneth细胞特异性功能；目标2：研究UPR在Paneth Cell中的作用 UFBP1缺乏引起的凋亡；目标3：阐明UFBP1消融诱导的机制 ER稳态的破坏。该项目的结果将提供对生理学的批判性见解这种重要的蛋白质修饰系统的功能和工作机制在维持肠道方面稳态，并对我们对Paneth细胞生物学的理解产生重大影响，发展炎性疾病的新型治疗靶标和ufmylation途径的生理功能以及与UPR的相互作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DDRGK1, a crucial player of ufmylation system, is indispensable for autophagic degradation by regulating lysosomal function.

DOI：
10.1038/s41419-021-03694-9
发表时间：
2021-04-20
期刊：
Cell death & disease
影响因子：
9
作者：
Cao Y;Li R;Shen M;Li C;Zou Y;Jiang Q;Liu S;Lu C;Li H;Liu H;Cai Y
通讯作者：
Cai Y

CDK5RAP3, a Novel Nucleoplasmic Shuttle, Deeply Regulates HSF1-Mediated Heat Stress Response and Protects Mammary Epithelial Cells from Heat Injury.

CDK5RAP3 是一种新型核质梭，深度调节 HSF1 介导的热应激反应并保护乳腺上皮细胞免受热损伤

DOI：
10.3390/ijms21218400
发表时间：
2020-11-09
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Shen Y;Zou Y;Li J;Chen F;Li H;Cai Y
通讯作者：
Cai Y

DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma.

DOI：
10.18632/oncotarget.20176
发表时间：
2017-09-29
期刊：
Oncotarget
影响因子：
0
作者：
Poole CJ;Zheng W;Lodh A;Yevtodiyenko A;Liefwalker D;Li H;Felsher DW;van Riggelen J
通讯作者：
van Riggelen J

ZBTB38, a novel regulator of autophagy initiation targeted by RB1CC1/FIP200 in spinal cord injury.