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

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $510,900

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10881883
- **Project number:** 5R35GM127073-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Susan D. Michaelis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $510,900
- **Award type:** 5
- **Project period:** 2018-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881883

## Citation

> US National Institutes of Health, RePORTER application 10881883, Role of the integral membrane protease ZMPSTE24 in membrane protein biogenesis and virus-host cell fusion (5R35GM127073-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10881883. Licensed CC0.

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