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Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation

Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of the viral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded by the host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1 IN degradation, we p...

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Autores principales: Ali, Hashim, Mano, Miguel, Braga, Luca, Naseem, Asma, Marini, Bruna, Vu, Diem My, Collesi, Chiara, Meroni, Germana, Lusic, Marina, Giacca, Mauro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389893/
https://www.ncbi.nlm.nih.gov/pubmed/30804369
http://dx.doi.org/10.1038/s41467-019-08810-0
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author Ali, Hashim
Mano, Miguel
Braga, Luca
Naseem, Asma
Marini, Bruna
Vu, Diem My
Collesi, Chiara
Meroni, Germana
Lusic, Marina
Giacca, Mauro
author_facet Ali, Hashim
Mano, Miguel
Braga, Luca
Naseem, Asma
Marini, Bruna
Vu, Diem My
Collesi, Chiara
Meroni, Germana
Lusic, Marina
Giacca, Mauro
author_sort Ali, Hashim
collection PubMed
description Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of the viral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded by the host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1 IN degradation, we performed a targeted RNAi screen using a library of siRNAs against all components of the ubiquitin-conjugation machinery using high-content microscopy. Here we report that the E3 RING ligase TRIM33 is a major determinant of HIV-1 IN stability. CD4-positive cells with TRIM33 knock down show increased HIV-1 replication and proviral DNA formation, while those overexpressing the factor display opposite effects. Knock down of TRIM33 reverts the phenotype of an HIV-1 molecular clone carrying substitution of IN serine 57 to alanine, a mutation known to impair viral DNA integration. Thus, TRIM33 acts as a cellular factor restricting HIV-1 infection by preventing provirus formation.
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spelling pubmed-63898932019-02-27 Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation Ali, Hashim Mano, Miguel Braga, Luca Naseem, Asma Marini, Bruna Vu, Diem My Collesi, Chiara Meroni, Germana Lusic, Marina Giacca, Mauro Nat Commun Article Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of the viral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded by the host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1 IN degradation, we performed a targeted RNAi screen using a library of siRNAs against all components of the ubiquitin-conjugation machinery using high-content microscopy. Here we report that the E3 RING ligase TRIM33 is a major determinant of HIV-1 IN stability. CD4-positive cells with TRIM33 knock down show increased HIV-1 replication and proviral DNA formation, while those overexpressing the factor display opposite effects. Knock down of TRIM33 reverts the phenotype of an HIV-1 molecular clone carrying substitution of IN serine 57 to alanine, a mutation known to impair viral DNA integration. Thus, TRIM33 acts as a cellular factor restricting HIV-1 infection by preventing provirus formation. Nature Publishing Group UK 2019-02-25 /pmc/articles/PMC6389893/ /pubmed/30804369 http://dx.doi.org/10.1038/s41467-019-08810-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ali, Hashim
Mano, Miguel
Braga, Luca
Naseem, Asma
Marini, Bruna
Vu, Diem My
Collesi, Chiara
Meroni, Germana
Lusic, Marina
Giacca, Mauro
Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
title Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
title_full Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
title_fullStr Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
title_full_unstemmed Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
title_short Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
title_sort cellular trim33 restrains hiv-1 infection by targeting viral integrase for proteasomal degradation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389893/
https://www.ncbi.nlm.nih.gov/pubmed/30804369
http://dx.doi.org/10.1038/s41467-019-08810-0
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