MARCH8 Inhibits Ebola Virus Glycoprotein, Human Immunodeficiency Virus Type 1 Envelope Glycoprotein, and Avian Influenza Virus H5N1 Hemagglutinin Maturation

Yu, Changqing; Li, Sunan; Zhang, Xianfeng; Khan, Ilyas; Ahmad, Iqbal; Zhou, Youwen; Li, Shuo; Shi, Jing; Wang, Yu; Zheng, Yong Hui

doi:10.1128/mbio.01882-20

Cited by 43 publications

(104 citation statements)

References 33 publications

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“…Our results show a broad antiviral activity of MARCH8 against the glycoproteins from three human viral pathogens-HIV-1, EboV, and SARS-CoV-2-and a primarily animal pathogen, VSV. MARCH8 targeting of HIV-1 Env, VSV-G, and, very recently, EboV-GP, has been reported (6,8,11,55,59). HIV-1 replicates predominantly in CD4 1 T cells and also infects MDMs (60).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Viral Glycoprotein Targeting by Membrane-Associated RING-CH Proteins

Lun

Waheed

Majadly

et al. 2021

mBio

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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.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Viral Glycoprotein Targeting by Membrane-Associated RING-CH Proteins

Lun

Waheed

Majadly

et al. 2021

mBio

View full text Add to dashboard Cite

show abstract

“…Our results show a broad antiviral activity of MARCH8 against the glycoproteins from three human viral pathogens – HIV-1, EboV, and SARS-CoV-2 – and a primarily animal pathogen, VSV. MARCH8 targeting of HIV-1 Env, VSV-G, and, very recently, EboV-GP, has been reported (6, 8, 11, 55, 59). HIV-1 replicates predominantly in CD4 + T cells and also infects MDM (60).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Viral Glycoprotein Targeting by Membrane-associated-RING-CH Proteins

Lun

Waheed

Majadly

et al. 2021

Preprint

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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.ImportanceViral envelope glycoproteins are an important structural component on the surface 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.

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“…The modification helps the proteins to adopt confirmation and ultimately help in replication as well as maturation. A few examples are: envelop protein of West Nile virus (WNV), Influenza, HIV-1, and ZIKV [ 105 , 106 , 107 ]. The importance of the glycosylation on envelop proteins can be understood from the fact that inhibition of glycosylation severely affects the maturation process in viruses such as Ebola, Influenza, HIV-1, and ZIKV [ 106 , 107 ].…”

Section: Carbohydrate-based Post-translational Modificationsmentioning

confidence: 99%

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

Kumar

Mehta

Mishra

et al. 2020

IJMS

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Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins’ functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.

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MARCH8 Inhibits Ebola Virus Glycoprotein, Human Immunodeficiency Virus Type 1 Envelope Glycoprotein, and Avian Influenza Virus H5N1 Hemagglutinin Maturation

Cited by 43 publications

References 33 publications

Mechanism of Viral Glycoprotein Targeting by Membrane-Associated RING-CH Proteins

Mechanism of Viral Glycoprotein Targeting by Membrane-Associated RING-CH Proteins

Mechanism of Viral Glycoprotein Targeting by Membrane-associated-RING-CH Proteins

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

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