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Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef

The serine incorporator (SERINC) protein family has five paralogous members with 9–11 transmembrane domains. SERINC5 is a potent host restriction factor and antagonized by HIV-1 Nef and two other retroviral accessory proteins via the lysosomal degradation pathway. Here, we investigated human SERINC4...

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Autores principales: Qiu, Xusheng, Eke, Ifeanyichukwu E., Johnson, Silas F., Ding, Chan, Zheng, Yong-Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842267/
https://www.ncbi.nlm.nih.gov/pubmed/33521797
http://dx.doi.org/10.1016/j.crviro.2020.100002
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author Qiu, Xusheng
Eke, Ifeanyichukwu E.
Johnson, Silas F.
Ding, Chan
Zheng, Yong-Hui
author_facet Qiu, Xusheng
Eke, Ifeanyichukwu E.
Johnson, Silas F.
Ding, Chan
Zheng, Yong-Hui
author_sort Qiu, Xusheng
collection PubMed
description The serine incorporator (SERINC) protein family has five paralogous members with 9–11 transmembrane domains. SERINC5 is a potent host restriction factor and antagonized by HIV-1 Nef and two other retroviral accessory proteins via the lysosomal degradation pathway. Here, we investigated human SERINC4 expression and antiviral mechanisms. Unlike its four paralogs, human SERINC4 is subjected to proteasome-mediated turnover, resulting in ~250-fold lower expression than SERINC5. However, when expression was normalized, human SERINC4 restricted HIV-1 replication as effectively as SERINC5, and SERINC4 was also antagonized by Nef via the lysosomal pathway. Although SERINC4 proteins are conserved within primates or rodents, their N-terminal regions are highly variable across species. Interestingly, unlike human SERINC4, murine SERINC4 was stably expressed but had a very poor antiviral activity. We created stable SERINC4 chimeras by replacing the N-terminal region and found that the 1–34 and 35–92 amino acids determine SERINC4 antiviral activity or protein expression, respectively. Using these chimeras, we demonstrate that SERINC4 is incorporated into HIV-1 virions and restricts Tier 1 HIV-1 more effectively than Tier 3 HIV-1. Importantly, SERINC4 increases HIV-1 sensitivity to broadly neutralizing antibodies. Thus, human SERINC4 strongly restricts HIV-1 replication when it is overexpressed, which reflects a potential antiviral activity of this gene product under physiological conditions.
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spelling pubmed-78422672021-01-28 Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef Qiu, Xusheng Eke, Ifeanyichukwu E. Johnson, Silas F. Ding, Chan Zheng, Yong-Hui Curr Res Virol Sci Article The serine incorporator (SERINC) protein family has five paralogous members with 9–11 transmembrane domains. SERINC5 is a potent host restriction factor and antagonized by HIV-1 Nef and two other retroviral accessory proteins via the lysosomal degradation pathway. Here, we investigated human SERINC4 expression and antiviral mechanisms. Unlike its four paralogs, human SERINC4 is subjected to proteasome-mediated turnover, resulting in ~250-fold lower expression than SERINC5. However, when expression was normalized, human SERINC4 restricted HIV-1 replication as effectively as SERINC5, and SERINC4 was also antagonized by Nef via the lysosomal pathway. Although SERINC4 proteins are conserved within primates or rodents, their N-terminal regions are highly variable across species. Interestingly, unlike human SERINC4, murine SERINC4 was stably expressed but had a very poor antiviral activity. We created stable SERINC4 chimeras by replacing the N-terminal region and found that the 1–34 and 35–92 amino acids determine SERINC4 antiviral activity or protein expression, respectively. Using these chimeras, we demonstrate that SERINC4 is incorporated into HIV-1 virions and restricts Tier 1 HIV-1 more effectively than Tier 3 HIV-1. Importantly, SERINC4 increases HIV-1 sensitivity to broadly neutralizing antibodies. Thus, human SERINC4 strongly restricts HIV-1 replication when it is overexpressed, which reflects a potential antiviral activity of this gene product under physiological conditions. 2020-12-08 2020 /pmc/articles/PMC7842267/ /pubmed/33521797 http://dx.doi.org/10.1016/j.crviro.2020.100002 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Qiu, Xusheng
Eke, Ifeanyichukwu E.
Johnson, Silas F.
Ding, Chan
Zheng, Yong-Hui
Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef
title Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef
title_full Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef
title_fullStr Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef
title_full_unstemmed Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef
title_short Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef
title_sort proteasomal degradation of human serinc4: a potent host anti-hiv-1 factor that is antagonized by nef
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842267/
https://www.ncbi.nlm.nih.gov/pubmed/33521797
http://dx.doi.org/10.1016/j.crviro.2020.100002
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