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Mechanism of Viral Glycoprotein Targeting by Membrane-Associated RING-CH Proteins
- Source :
- bioRxiv, article-version (status) pre, article-version (number) 2, mBio, Vol 12, Iss 2 (2021)
- Publication Year :
- 2021
-
Abstract
- An emerging class of cellular inhibitory proteins has been identified that targets viral glycoproteins. These include the membrane-associated RING-CH (MARCH) family of E3 ubiquitin ligases that, among other functions, downregulate cell surface proteins involved in adaptive immunity. The RING-CH domain of MARCH proteins is thought to function by catalyzing the ubiquitination of the cytoplasmic tails (CTs) of target proteins, leading to their degradation. MARCH proteins have recently been reported to target retroviral envelope glycoproteins (Env) and vesicular stomatitis virus G glycoprotein (VSV-G). However, the mechanism of antiviral activity remains poorly defined. Here we show that MARCH8 antagonizes the full-length forms of HIV-1 Env, VSV-G, Ebola virus glycoprotein (EboV-GP), and the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thereby impairing the infectivity of virions pseudotyped with these viral glycoproteins. This MARCH8-mediated targeting of viral glycoproteins requires the E3 ubiquitin ligase activity of the RING-CH domain. We observe that MARCH8 protein antagonism of VSV-G is CT dependent. In contrast, MARCH8-mediated targeting of HIV-1 Env, EboV-GP, and SARS-CoV-2 S protein by MARCH8 does not require the CT, suggesting a novel mechanism of MARCH-mediated antagonism of these viral glycoproteins. Confocal microscopy data demonstrate that MARCH8 traps the viral glycoproteins in an intracellular compartment. We observe that the endogenous expression of MARCH8 in several relevant human cell types is rapidly inducible by type I interferon. These results help to inform the mechanism by which MARCH proteins exert their antiviral activity and provide insights into the role of cellular inhibitory factors in antagonizing the biogenesis, trafficking, and virion incorporation of viral glycoproteins.IMPORTANCE Viral envelope glycoproteins are an important structural component on the surfaces of enveloped viruses that direct virus binding and entry and also serve as targets for the host adaptive immune response. In this study, we investigate the mechanism of action of the MARCH family of cellular proteins that disrupt the trafficking and virion incorporation of viral glycoproteins across several virus families. This research provides novel insights into how host cell factors antagonize viral replication, perhaps opening new avenues for therapeutic intervention in the replication of a diverse group of highly pathogenic enveloped viruses.
- Subjects :
- viruses
Ubiquitin-Protein Ligases
Intracellular Space
cellular inhibitory factors
medicine.disease_cause
Virus Replication
spike protein
Microbiology
Article
03 medical and health sciences
HIV-1 Env
Ubiquitin
Viral envelope
Species Specificity
Viral Envelope Proteins
Interferon
Virology
medicine
Humans
RNA Viruses
Amino Acid Sequence
VSV-G
Cells, Cultured
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Ebola virus
Ebola virus GP
biology
SARS-CoV-2
030302 biochemistry & molecular biology
Virion
Membrane Proteins
biology.organism_classification
QR1-502
Ubiquitin ligase
Cell biology
HEK293 Cells
chemistry
Viral replication
Gene Expression Regulation
E3 ubiquitin ligase
Vesicular stomatitis virus
Mutation
biology.protein
Interferons
Glycoprotein
viral glycoproteins
medicine.drug
Subjects
Details
- ISSN :
- 21507511
- Volume :
- 12
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- mBio
- Accession number :
- edsair.doi.dedup.....ad05c9e0a0aada30ee0da47b5a4d2326