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

Hashim Ali; Miguel Mano; Luca Braga; Asma Naseem; Bruna Marini; Diem My Vu; Chiara Collesi; Germana Meroni; Marina Lusic; Mauro Giacca

doi:10.1038/s41467-019-08810-0

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

Hashim Ali, Miguel Mano, Luca Braga, Asma Naseem, Bruna Marini, Diem My Vu, Chiara Collesi, Germana Meroni, Marina Lusic, Mauro Giacca^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	926
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	10
Issue number	1
Early online date	25 Feb 2019
DOIs	https://doi.org/10.1038/s41467-019-08810-0
Publication status	Published - 25 Feb 2019

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Cellular TRIM33 restrains HIV-1_ALI_Accepted23January2019_GOLD VoRFinal published version, 2.73 MBLicence: CC BY

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abstract = "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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AU - Ali, Hashim

AU - Mano, Miguel

AU - Braga, Luca

AU - Naseem, Asma

AU - Marini, Bruna

AU - Vu, Diem My

AU - Collesi, Chiara

AU - Meroni, Germana

AU - Lusic, Marina

AU - Giacca, Mauro

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

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