Elucidating the Antiviral Mechanism of Different MARCH Factors.

Brian Lynch,Brandon Waxman,Supawadee Umthong,Stacy M. Horner,Spyridon Stavrou,Emily B. Ivey,Uddhav Timilsina

doi:10.1128/mbio.03264-20

Brian Lynch, Brandon Waxman + Show 5 more

Open Access

https://doi.org/10.1128/mbio.03264-20

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Journal: mBio	Publication Date: Mar 2, 2021
Citations: 17	License type: CC BY 4.0

Affiliation: University at Buffalo, State University of New York

Abstract

The membrane-associated RING-CH (MARCH) proteins belong to a family of E3 ubiquitin ligases, whose main function is to remove transmembrane proteins from the plasma membrane. Recent work has shown that the human MARCH1, 2, and 8 are antiretroviral factors that target the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins by reducing their incorporation in the budding virions. Nevertheless, the dearth of information regarding the antiviral mechanism of this family of proteins necessitates further examination. In this study, using both the human MARCH proteins and their mouse homologues, we provide a comprehensive analysis of the antiretroviral mechanism of this family of proteins. Moreover, we show that human MARCH proteins restrict to various degrees the envelope glycoproteins of a diverse number of viruses. This report sheds light on the important antiviral function of MARCH proteins and their significance in cell intrinsic immunity.IMPORTANCE This study examines the mechanism utilized by different MARCH proteins to restrict retrovirus infection. MARCH proteins block the incorporation of envelope glycoproteins to the budding virions. In this report, by comparing the human and mouse MARCH genes and using murine leukemia virus (MLV) and HIV-1, we identify differences in the mechanism of restriction among MARCH proteins. Furthermore, we perform a comprehensive analysis on a number of envelope glycoproteins and show that MARCH proteins have broad antiviral functions.

Highlights

The membrane-associated RING-CH (MARCH) proteins belong to a family of E3 ubiquitin ligases, whose main function is to remove transmembrane proteins from the plasma membrane
Using a variety of viral envelope glycoproteins, we demonstrated that human MARCH proteins have broad antiviral functions and target for degradation a variety of viral glycoproteins including those of lymphocytic choriomeningitis virus (LCMV), Lassa virus (LASV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
We found that mouse March1 was expressed only in MutuDC1940, bone marrow-derived dendritic cells (BMDCs), and bone marrow-derived macrophages (BMDMs) while mouse March2 and March8 were expressed in all cell lines tested (Fig. 1A to C and Fig. S1A and B in the supplemental material)

Summary

Introduction

The membrane-associated RING-CH (MARCH) proteins belong to a family of E3 ubiquitin ligases, whose main function is to remove transmembrane proteins from the plasma membrane. In this study, using both the human MARCH proteins and their mouse homologues, we provide a comprehensive analysis of the antiretroviral mechanism of this family of proteins. By comparing the human and mouse MARCH genes and using murine leukemia virus (MLV) and HIV-1, we identify differences in the mechanism of restriction among MARCH proteins. The viral envelope is critical for viral replication and spread and a possible target for host antiviral factors Such factors include the members of the membraneassociated RING-CH (MARCH) protein family, a unique family of E3 protein ligases, which target a number of immune receptors found in the plasma membrane (PM) [1]. Additional domains have been identified in MARCH1 and MARCH8 to be important for their function including a domain in between the RING-CH domain and the transmembrane domain (DIRT domain), a short C-terminal sequence (VQNC), which is important for the proper folding of MARCH1 and MARCH8, and two C-terminal cytoplasmic tyrosine endocytic motifs (YXXU) [15, 18,19,20,21,22]

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