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

• 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
• 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

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.

项目总结

项目成果

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

• DOI: 10.1080/19491034.2023.2288476
• 发表时间: 2023-12
• 期刊: Nucleus (Austin, Tex.)

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

• DOI: 10.1074/jbc.ra120.015792
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Babatz TD;Spear ED;Xu W;Sun OL;Nie L;Carpenter EP;Michaelis S
• 通讯作者: Michaelis S

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

• DOI: 10.1371/journal.pone.0239269
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wood KM;Spear ED;Mossberg OW;Odinammadu KO;Xu W;Michaelis S
• 通讯作者: Michaelis S

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

• DOI: 10.1073/pnas.2118695119
• 发表时间: 2022-03-01
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Wang Y;Shilagardi K;Hsu T;Odinammadu KO;Maruyama T;Wu W;Lin CS;Damoci CB;Spear ED;Shin JY;Hsu W;Michaelis S;Worman HJ
• 通讯作者: Worman HJ

Prelamin A and ZMPSTE24 in premature and physiological aging.

• DOI: 10.1080/19491034.2023.2270345
• 发表时间: 2023-12
• 期刊: Nucleus (Austin, Tex.)