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Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation

ERα相关降解对节律性 m6A RNA 修饰的调节

基本信息

批准号：
10297978
负责人：
Deyu Fang
金额：
$ 57.48万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297978
关键词：
Address Animal Model Apoptosis Binding Cellular Metabolic Process Circadian Rhythms Cues Cytosol Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Enzymes Fatty Liver Genetic Engineering Genetic Translation Goals Hepatic High Fat Diet Homeostasis Human Hyperlipidemia Knockout Mice Light Lipids Liver Mediating Messenger RNA Metabolic Metabolic Control Metabolic Diseases Metabolism Methylation Modification Molecular Monitor Mus Pathway interactions Periodicity Physiological Physiological Processes Play Polyubiquitination Process Protein Family Proteins Quality Control RNA Reader Regulation Risk Role Signal Transduction Pathway Testing Therapeutic Time-restricted feeding Translations Ubiquitination circadian circadian pacemaker knock-down lipid metabolism mRNA Stability metabolic phenotype misfolded protein non-alcoholic fatty liver disease novel preservation programs ubiquitin-protein ligase

项目摘要

Endoplasmic Reticulum (ER)-Associated Degradation (ERAD) is a major ER quality-control program that monitors and translocates unfolded or misfolded protein substrates from the ER to cytosol for polyubiquitination and proteasomal degradation. N6-methyladenosine (m6A) methylation, the most prevalent internal modification of mammalian mRNAs, is known to regulate the stability, translation, and function of almost every major class of human RNAs. Three major families of proteins, including writers, readers, and erasers, are known to be responsible for the reversible RNA m6A methylation process. However, the signal transduction pathway underlying the regulation of RNA m6A modification remain elusive. Herein, we accumulated strong preliminary evidence for an unprecedented circadian-regulated ERAD pathway that controls mRNA m6A modification and subsequent lipid homeostasis, which we called “circadian ERAD-m6A”. Our major preliminary findings include: (i) the ER-resident E3 ubiquitin ligase HRD1 and its co-factor SEL1L, the major components of ERAD machinery, are regulated by the circadian clock in the liver; (ii) HRD1 interacts with and mediates polyubiquitination and degradation of the specific m6A writer METTL14 and the reader YTHDF3; (iii) HRD1 liver-specific KO (LKO) mice display reversed fashions with METTL14-LKO or YTHDF3-knockdown mice in hepatic m6A mRNA methylation levels, expression of lipid metabolic regulators, and metabolic phenotypes associated with hepatic steatosis and hyperlipidemia; and (iv) unlike the classic ERAD, the newly-identified ERAD-m6A regulatory axis and its function in hepatic lipid metabolism are under the control of circadian rhythm. These observations led to our central hypothesis that the liver HRD1-ERAD program, which is oscillated under the circadian clock, regulates hepatic m6A RNA modification by controlling rhythmic degradation of the specific m6A writer METTL14 and the reader YTHDF3. This unprecedented circadian ERAD-m6A RNA modification regulatory network, which may be dysregulated by circadian-disrupting cues, represents a major pathway that controls metabolic homeostasis associated with hepatic steatosis and hyperlipidemia. In this application, we will utilize molecular and cellular approaches, genetically engineered animal models, and high-throughput profiling of m6A RNA modification to critically address the function and mechanism by which circadian ERAD regulates hepatic m6A RNA modification and lipid metabolism. In two aims, we will: 1) define a novel circadian ERAD pathway that modulates rhythmic m6A RNA modification through degrading the specific m6A writer and reader; and 2) determine the functional significance of circadian ERAD-m6A RNA modification pathway in maintaining lipid homeostasis. Upon completion of this project, we will reveal the function and mechanism by which a novel circadian ERAD-m6A RNA modification pathway regulates lipid homeostasis associated with metabolic disorders. The findings will open up new paradigms for the studies on the physiological ERAD and m6A RNA modification and shed new light on developing therapeutics for metabolic disease.

内质网(ERAD) -相关降解（ERAD）是内质网质量控制的主要程序