Role of the integral membrane protease ZMPSTE24 in membrane protein biogenesis and virus-host cell fusion

整合膜蛋白酶 ZMPSTE24 在膜蛋白生物发生和病毒-宿主细胞融合中的作用

基本信息

批准号：
10622926
负责人：
Susan D. Michaelis
金额：
$ 51.09万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622926
关键词：
Antiviral Agents Biogenesis Biological Biology COVID-19 pandemic Cell fusion Cell membrane Cells Cellular Membrane Cytoprotection Defect Disease Endoplasmic Reticulum Ensure Environment Goals Health Human IFITM1 gene Infection Integral Membrane Protein Interferons Laboratories Lamin Type A Lead Lipid Bilayers Longevity Longitudinal Studies Membrane Membrane Lipids Membrane Proteins Metalloproteases Mus Nuclear Matrix-Associated Proteins Pathway interactions Peptide Hydrolases Positioning Attribute Post-Translational Protein Processing Premature aging syndrome Progeria Property Proteins Proteolytic Processing Proteome Quality Control Research Role Viral Viral Physiology Virus Virus Diseases Zinc antiviral drug development biophysical properties farnesylation fluidity insight membrane activity novel overexpression prelamin A recruit trafficking

项目摘要

PROJECT SUMMARY A significant fraction of the eukaryotic proteome is composed of integral membrane proteins, most of which are inserted and assembled at the endoplasmic reticulum (ER). The diverse biophysical characteristics, topology, posttranslational modifications, and activities of these membrane proteins necessitate distinct cellular pathways and numerous components to ensure their proper biogenesis and function. The goal of this project is to define a new mechanistic role of the zinc metalloprotease ZMPSTE24 in membrane protein biology. ZMPSTE24 has long been a research focus in my laboratory and is important for human health and longevity through its established role in the proteolytic processing of farnesylated prelamin A, precursor of the nuclear scaffold protein lamin A. Defects in this processing step lead to premature aging (progeria) diseases. However, an intriguing new function for ZMPSTE24 in viral defense was recently discovered by others and surprisingly does not require its catalytic activity: ZMPSTE24 confers potent antiviral activity against many enveloped viruses through its interaction with a class of small membrane proteins called interferon-induced transmembrane proteins (IFITM1, 2, and 3). The IFITMs block virus-host cell fusion by a mechanism that involves “rigidifying” host cell membranes. As is the case for IFITMs, the overexpression of ZMPSTE24 robustly protects cells from infection by enveloped viruses, and its proteolytic activity is not needed in this role. Furthermore, depletion of ZMPSTE24 in cells and mice cause them to succumb to viral infection. These findings place ZMPSTE24 at an important position in the cell’s first line of defense against viral infection, likely through a general cell biological role. Here we hypothesize that ZMPSTE24 defines a central component in a known or new pathway for membrane protein biogenesis (insertion, topology, stability/quality control, posttranslational modification, or oligomerization), with IFITM3 as its substrate. Alternatively, ZMPSTE24 may facilitate IFITM3’s membrane rigidifying function in some other way, directly by recruitment to IFITM3, or indirectly by altering the composition or properties of the lipid bilayer. This project represents an exciting new direction in my laboratory’s long-term studies of ZMPSTE24, inspired by the convergence of ZMPSTE24’s newly discovered role in viral defense and the COVID-19 pandemic. Nevertheless, the studies we propose also relate to earlier research in my laboratory on membrane protein topology, trafficking, and ER quality control. Deciphering the antiviral role of ZMPSTE24 via the IFITMs presents an intriguing puzzle that we are primed to solve. We expect the studies proposed here will uncover a new fundamental role(s) for ZMPSTE24 in membrane protein biogenesis or membrane lipid composition or fluidity. Furthermore, insight into the mechanism whereby ZMPSTE24 enables IFITMs to block virus-host-cell fusion could ultimately be harnessed to develop a novel anti-viral drug.

项目概要真核蛋白质组的很大一部分由整合膜蛋白组成，其中大部分在内质网（ER）处插入并组装不同的生物物理特征，这些膜蛋白的拓扑结构、翻译后修饰和活性需要不同的细胞该项目的目标是确保其正确的生物发生和功能。是为了定义锌金属蛋白酶 ZMPSTE24 在膜蛋白中的新机制作用 ZMPSTE24 长期以来一直是我实验室的研究重点，对人类健康和健康非常重要。通过其在法尼基化前核纤蛋白 A 的蛋白水解过程中发挥的既定作用（核支架蛋白核纤层蛋白 A。此加工步骤中的缺陷会导致过早衰老（早衰）疾病。然而，最近其他人发现了 ZMPSTE24 在病毒防御中的一个有趣的新功能令人惊讶的是不需要其催化活性：ZMPSTE24 赋予针对许多病毒的有效抗病毒活性有包膜病毒通过与一类称为干扰素诱导的小膜蛋白相互作用跨膜蛋白（IFITM1、2 和 3） IFITM 通过以下机制阻止病毒与宿主细胞融合。与 IFITM 的情况一样，ZMPSTE24 的过度表达涉及“硬化”宿主细胞膜。强有力地保护细胞免受包膜病毒的感染，并且其蛋白水解活性在该作用中不是必需的。此外，细胞和小鼠中 ZMPSTE24 的缺失会导致它们死于病毒感染。研究结果表明 ZMPSTE24 在细胞抵御病毒感染的第一道防线中处于重要位置通过一般细胞生物学作用。在这里，我们发现 ZMPSTE24 定义了已知或新途径中的一个核心组件膜蛋白生物合成（插入、拓扑、稳定性/质量控制、翻译后或者，ZMPSTE24 可以促进 IFITM3 作为其底物。 IFITM3 的膜硬化功能以其他方式发挥作用，直接通过 IFITM3 募集，或通过改变脂质双层的组成或特性来间接地实现这一目标是一个令人兴奋的项目。受到 ZMPSTE24 融合的启发，我的实验室对 ZMPSTE24 进行长期研究的新方向尽管如此，我们提出的研究还是在病毒防御和 COVID-19 大流行中新发现的作用。与我实验室早期关于膜蛋白拓扑、运输和 ER 质量控制的研究相关。通过 IFITM 破译 ZMPSTE24 的抗病毒作用提出了一个有趣的难题，我们准备好解决这个难题我们预计这里提出的研究将揭示 ZMPSTE24 在以下方面的新的基本作用。膜蛋白生物发生或膜脂质组成或流动性此外，深入了解膜蛋白生物发生或膜脂质组成或流动性。最终可以利用 ZMPSTE24 使 IFITM 阻止病毒-宿主-细胞融合的机制开发一种新型抗病毒药物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B.

法尼基转移酶抑制剂 (FTI) lonafarnib 可改善早衰症 MAD-B 患者的 ZMPSTE24 缺陷成纤维细胞的核形态。

DOI：
发表时间：
2023-12
期刊：
影响因子：
0
作者：
Odinammadu, Kamsi O;Shilagardi, Khurts;Tuminelli, Kelsey;Judge, Daniel P;Gordon, Leslie B;Michaelis, Susan
通讯作者：
Michaelis, Susan

Defining substrate requirements for cleavage of farnesylated prelamin A by the integral membrane zinc metalloprotease ZMPSTE24.

定义整合膜锌金属蛋白酶 ZMPSTE24 裂解法尼基化前核纤层蛋白 A 的底物要求。

DOI：
发表时间：
2020
期刊：
影响因子：
3.7
作者：
Wood, Kaitlin M;Spear, Eric D;Mossberg, Otto W;Odinammadu, Kamsi O;Xu, Wenxin;Michaelis, Susan
通讯作者：
Michaelis, Susan

Site specificity determinants for prelamin A cleavage by the zinc metalloprotease ZMPSTE24.

锌金属蛋白酶 ZMPSTE24 切割前核纤层蛋白 A 的位点特异性决定因素。

DOI：
发表时间：
2021-01
期刊：
影响因子：
0
作者：
Babatz, Timothy D;Spear, Eric D;Xu, Wenxin;Sun, Olivia L;Nie, Laiyin;Carpenter, Elisabeth P;Michaelis, Susan
通讯作者：
Michaelis, Susan

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice.

消除 prelamin A ZMPSTE24 裂解位点会导致小鼠出现早衰表型，且寿命接近正常。

DOI：
发表时间：
2022-03-01
期刊：
影响因子：
11.1
作者：
Wang, Yuexia;Shilagardi, Khurts;Hsu, Trunee;Odinammadu, Kamsi O;Maruyama, Takamitsu;Wu, Wei;Lin, Chyuan;Damoci, Christopher B;Spear, Eric D;Shin, Ji;Hsu, Wei;Michaelis, Susan;Worman, Howard J
通讯作者：
Worman, Howard J

Prelamin A and ZMPSTE24 in premature and physiological aging.

Prelamin A 和 ZMPSTE24 在过早衰老和生理衰老中的作用。