Cargando…
Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain
MARCH1 and MARCH8 are closely related E3 ubiquitin ligases that ubiquitinate an overlapping spectrum of host proteins and restrict replication of certain viruses. While the antiviral activity of MARCH8 has been intensively studied, less is known regarding virus inhibition by MARCH1. Isoforms 1 and 2...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697684/ https://www.ncbi.nlm.nih.gov/pubmed/36423158 http://dx.doi.org/10.3390/v14112549 |
_version_ | 1784838627784654848 |
---|---|
author | Villalón-Letelier, Fernando Farrukee, Rubaiyea Londrigan, Sarah L. Brooks, Andrew G. Reading, Patrick C. |
author_facet | Villalón-Letelier, Fernando Farrukee, Rubaiyea Londrigan, Sarah L. Brooks, Andrew G. Reading, Patrick C. |
author_sort | Villalón-Letelier, Fernando |
collection | PubMed |
description | MARCH1 and MARCH8 are closely related E3 ubiquitin ligases that ubiquitinate an overlapping spectrum of host proteins and restrict replication of certain viruses. While the antiviral activity of MARCH8 has been intensively studied, less is known regarding virus inhibition by MARCH1. Isoforms 1 and 2 of MARCH1 are very similar in overall structure but show major differences in their N-terminal cytoplasmic domain (N-CT). Herein, we used a doxycycline-inducible overexpression system to demonstrate that MARCH1.1 reduces titres of influenza A virus (IAV) released from infected cells whereas MARCH1.2 does not. The deletion of the entire N-CT of MARCH1.2 restored its ability to restrict IAV infectivity and sequential deletions mapped the restoration of IAV inhibition to delete the 16 N-terminal residues within the N-CT of MARCH1.2. While only MARCH1.1 mediated anti-IAV activity, qPCR demonstrated the preferential expression of MARCH1.2 over MARCH1.1 mRNA in unstimulated human peripheral blood mononuclear cells and also in monocyte-derived macrophages. Together, these studies describe the differential ability of MARCH1 isoforms to restrict IAV infectivity for the first time. Moreover, as published immunological, virological and biochemical studies examining the ability of MARCH1 to target particular ligands generally use only one of the two isoforms, these findings have broader implications for our understanding of how MARCH1 isoforms might differ in their ability to modulate particular host and/or viral proteins. |
format | Online Article Text |
id | pubmed-9697684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96976842022-11-26 Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain Villalón-Letelier, Fernando Farrukee, Rubaiyea Londrigan, Sarah L. Brooks, Andrew G. Reading, Patrick C. Viruses Article MARCH1 and MARCH8 are closely related E3 ubiquitin ligases that ubiquitinate an overlapping spectrum of host proteins and restrict replication of certain viruses. While the antiviral activity of MARCH8 has been intensively studied, less is known regarding virus inhibition by MARCH1. Isoforms 1 and 2 of MARCH1 are very similar in overall structure but show major differences in their N-terminal cytoplasmic domain (N-CT). Herein, we used a doxycycline-inducible overexpression system to demonstrate that MARCH1.1 reduces titres of influenza A virus (IAV) released from infected cells whereas MARCH1.2 does not. The deletion of the entire N-CT of MARCH1.2 restored its ability to restrict IAV infectivity and sequential deletions mapped the restoration of IAV inhibition to delete the 16 N-terminal residues within the N-CT of MARCH1.2. While only MARCH1.1 mediated anti-IAV activity, qPCR demonstrated the preferential expression of MARCH1.2 over MARCH1.1 mRNA in unstimulated human peripheral blood mononuclear cells and also in monocyte-derived macrophages. Together, these studies describe the differential ability of MARCH1 isoforms to restrict IAV infectivity for the first time. Moreover, as published immunological, virological and biochemical studies examining the ability of MARCH1 to target particular ligands generally use only one of the two isoforms, these findings have broader implications for our understanding of how MARCH1 isoforms might differ in their ability to modulate particular host and/or viral proteins. MDPI 2022-11-18 /pmc/articles/PMC9697684/ /pubmed/36423158 http://dx.doi.org/10.3390/v14112549 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Villalón-Letelier, Fernando Farrukee, Rubaiyea Londrigan, Sarah L. Brooks, Andrew G. Reading, Patrick C. Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain |
title | Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain |
title_full | Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain |
title_fullStr | Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain |
title_full_unstemmed | Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain |
title_short | Isoforms of Human MARCH1 Differ in Ability to Restrict Influenza A Viruses Due to Differences in Their N Terminal Cytoplasmic Domain |
title_sort | isoforms of human march1 differ in ability to restrict influenza a viruses due to differences in their n terminal cytoplasmic domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697684/ https://www.ncbi.nlm.nih.gov/pubmed/36423158 http://dx.doi.org/10.3390/v14112549 |
work_keys_str_mv | AT villalonletelierfernando isoformsofhumanmarch1differinabilitytorestrictinfluenzaavirusesduetodifferencesintheirnterminalcytoplasmicdomain AT farrukeerubaiyea isoformsofhumanmarch1differinabilitytorestrictinfluenzaavirusesduetodifferencesintheirnterminalcytoplasmicdomain AT londrigansarahl isoformsofhumanmarch1differinabilitytorestrictinfluenzaavirusesduetodifferencesintheirnterminalcytoplasmicdomain AT brooksandrewg isoformsofhumanmarch1differinabilitytorestrictinfluenzaavirusesduetodifferencesintheirnterminalcytoplasmicdomain AT readingpatrickc isoformsofhumanmarch1differinabilitytorestrictinfluenzaavirusesduetodifferencesintheirnterminalcytoplasmicdomain |