Novel mechanisms of UPR sensing and nonalcoholic fatty liver disease

UPR传感和非酒精性脂肪肝的新机制

• 批准号: 9026108
• 负责人: Zihai Li
• 金额: $ 33.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026108
• 关键词: Address; Adopted; Apoptotic; Awards and Prizes; Binding; Biochemical; Biogenesis; Biology; Calcium; Cell Death; Cells; Cessation of life; Characteristics; Data; Dimerization; Disease; Dissociation; Endoplasmic Reticulum; Ensure; Epidemic; Eukaryotic Cell; Fatty Liver; Hepatology; High Fat Diet; Homeostasis; Homo; Incidence; Knock-out; Knockout Mice; Lead; Light; Link; Lipoproteins; Liver; Liver diseases; Low Density Lipoprotein Receptor; Medicine; Membrane; Mitochondria; Modeling; Molecular; Molecular Chaperones; Morus; Mus; Obesity; Pathogenesis; Pathway interactions; Physiology; Proteins; Public Health; Published Comment; Quality Control; Research; Research Personnel; Role; Signal Transduction; Stress; System; Time; Transactivation; Update; Work; endoplasmic reticulum stress; lipid biosynthesis; lipid metabolism; liver function; non-alcoholic fatty liver; novel; overexpression; pandemic disease; programs; protein misfolding; public health relevance; response; sensor; structural biology; success

 DESCRIPTION (provided by applicant): This project addresses the mechanism of unfolded protein response (UPR) and non-alcoholic fatty liver disease (NAFLD). Upon accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER), eukaryotic cells adopt a conserved and fundamentally important UPR pathway to turn on the expression of major ER chaperones and proteins involved in ER-associated degradation to alleviate stress. This critical protein quality control mechanism is transmitted by three ER trans-membrane UPR sensors including IRE1, PERK and ATF6. The significance of UPR research is far-reaching in medicine; it is highlighted and supported by the 2014 Albert Lasker Prize awarded to Drs. Kazutoshi Mori and Peter Walter. The mechanism whereby UPR sensors are triggered however remains a subject of intense debate, which is important to resolve given the ubiquitous implication of UPR in physiology and diseases. Present models include direct binding of ER sensors by misfolded proteins and dissociation of Grp78 from the luminal domains of ER sensors. Neither of the models sufficiently explains the exquisite sensitivity and high efficiency of the system which allows cells to react and adapt to stress in real time. We have produced an exciting body of evidence implicating CNPY2, a previously unknown ER protein in UPR, in activating all three UPR sensors in response to ER stress. CNPY2 is highly expressed in the liver in the steady state and can be further induced by UPR via direct transactivation by CHOP. Knockout (KO) of cnpy2 from mice silences UPR pathways, blocks CHOP expression, and protects cells from UPR-induced cell death. Remarkably, the KO mice are rendered highly protective against high fat diet (HFD)-induced ER stress and non-alcoholic fatty liver disease (NAFLD). In turn, CNPY2 overexpression increases the UPR and apoptotic signals in cells upon ER stress induction. Thus, a novel model of UPR sensing that involves CNPY2 is emerging. We hypothesize that CNPY2 is a critical positive initiator for general UPR in the liver, and that it i required for ER stress-induced NAFLD. We propose two specific aims to address our hypothesis. Aim 1 will determine the molecular mechanism of CNPY2- regulated UPR initiation, using biochemical, biophysical and structural approaches. Aim 2 will be focused on untangling the mechanisms of CNPY2 in regulating hepatosteatosis by systemically studying the roles of CNPY2 in: 1) lipogenesis and lipid metabolism; 2) regulating lipoprotein secretion and the biogenesis of LDL receptor; 3) controlling calcium homeostasis related to mitochondria-ER cross-talk. Collectively, this proposal shall have a significant impact in understanding the mechanism of UPR sensing, and the pathogenesis of NAFLD.

 描述（由适用提供）：该项目介绍了展开的蛋白质反应（UPR）和非酒精性脂肪肝病（NAFLD）的机制。在内质网（ER）的腔中积聚了未折叠或错误折叠的蛋白质后，真核细胞采用保守且根本上重要的UPR途径来打开与ER相关降解相关的主要ER伴侣和蛋白质的表达，以减轻应激。蛋白质质量控​​制机制是由包括IRE1，PERK和ATF6在内的三个ER跨膜UPR传感器传输的。 UPR研究的重要性在医学方面具有深远的影响。它得到了DRS授予的2014年Albert Lasker奖的强调和支持。 Kazutoshi Mori和Peter Walter。然而，触发UPR传感器的机制仍然是激烈争论的主题，鉴于UPR在生理和疾病中的无处不在含义，这对于解决非常重要。目前的模型包括通过错误折叠的蛋白质直接结合ER传感器以及GRP78与ER传感器的腔内结构域的解离。这两个模型都没有充分解释系统的独家灵敏度和高效率，该系统允许细胞实时反应并适应压力。我们已经在UPR中产生了一个令人兴奋的证据含义CNPY2，这是一种以前未知的ER蛋白，在激活所有三个UPR传感器时都响应于ER应力。 CNPY2在稳态中高度表达在肝脏中，可以通过CHOP直接反式激活来进一步诱导。 CNPY2的敲除（KO）沉默UPR途径，阻止CHOP表达，并保护细胞免受UPR诱导的细胞死亡的影响。值得注意的是，KO小鼠对高脂肪饮食（HFD）诱导的ER应激和非酒精性脂肪肝疾病（NAFLD）的高度保护。反过来，CNPY2的过表达在ER应激诱导后增加了细胞中的UPR和凋亡信号。这是涉及CNPY2的新型UPR敏感性模型正在出现。我们假设CNPY2是肝脏中通用UPR的关键阳性引发剂，并且是ER应力诱导的NAFLD所必需的。我们提出了两个具体的目的来解决我们的假设。目标1）脂肪生成和脂质代谢； 2）调节性脂蛋白分泌和LDL受体的生物发生； 3）控制与线粒体-er串扰有关的钙稳态。总的来说，该提案应对理解UPR感应机理以及NAFLD的发病机理产生重大影响。