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HIV relies on neddylation for ubiquitin ligase-mediated functions
BACKGROUND: HIV and SIV defeat antiviral proteins by usurping Cullin-RING E3 ubiquitin ligases (CRLs) and likely influence other cellular processes through these as well. HIV-2 viral protein X (Vpx) engages the cullin4-containing CRL4 complex to deplete the antiviral protein SAMHD1. Vif expressed by...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842660/ https://www.ncbi.nlm.nih.gov/pubmed/24245672 http://dx.doi.org/10.1186/1742-4690-10-138 |
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author | Nekorchuk, Michael D Sharifi, Hamayun J Furuya, Andrea KM Jellinger, Robert de Noronha, Carlos MC |
author_facet | Nekorchuk, Michael D Sharifi, Hamayun J Furuya, Andrea KM Jellinger, Robert de Noronha, Carlos MC |
author_sort | Nekorchuk, Michael D |
collection | PubMed |
description | BACKGROUND: HIV and SIV defeat antiviral proteins by usurping Cullin-RING E3 ubiquitin ligases (CRLs) and likely influence other cellular processes through these as well. HIV-2 viral protein X (Vpx) engages the cullin4-containing CRL4 complex to deplete the antiviral protein SAMHD1. Vif expressed by HIV-1 and HIV-2 taps a cullin5 ubiquitin ligase complex to mark the antiviral protein APOBEC3G for destruction. Viral Protein R of HIV-1 (Vpr) assembles with the CRL4 ubiquitin ligase complex to deplete uracil-N-glycosylase2 (UNG2). Covalent attachment of the ubiquitin-like protein side-chain NEDD8 functionally activates cullins which are common to all of these processes. RESULTS: The requirement for neddylation in HIV-1 and HIV-2 infectivity was tested in the presence of APOBEC3G and SAMHD1 respectively. Further the need for neddylation in HIV-1 Vpr-mediated depletion of UNG2 was probed. Treatment with MLN4924, an adenosine sulfamate analog which hinders the NEDD8 activating enzyme NAE1, blocked neddylation of cullin4A (CUL4A). The inhibitor hindered HIV-1 infection in the presence of APOBEC3G, even when Vif was expressed, and it stopped HIV-2 infection in the presence of SAMHD1 and Vpx. Consistent with these findings, MLN4924 prevented Vpx-mediated depletion of SAMHD1 in macrophages infected with Vpx-expressing HIV-2, as well as HIV-1 Vif-mediated destruction of APOBEC3G. It also stemmed Vpr-mediated UNG2 elimination from cells infected with HIV-1. CONCLUSIONS: Neddylation plays an important role in HIV-1 and HIV-2 infection. This observation is consistent with the essential parts that cullin-based ubiquitin ligases play in overcoming cellular anti-viral defenses. |
format | Online Article Text |
id | pubmed-3842660 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-38426602013-11-29 HIV relies on neddylation for ubiquitin ligase-mediated functions Nekorchuk, Michael D Sharifi, Hamayun J Furuya, Andrea KM Jellinger, Robert de Noronha, Carlos MC Retrovirology Research BACKGROUND: HIV and SIV defeat antiviral proteins by usurping Cullin-RING E3 ubiquitin ligases (CRLs) and likely influence other cellular processes through these as well. HIV-2 viral protein X (Vpx) engages the cullin4-containing CRL4 complex to deplete the antiviral protein SAMHD1. Vif expressed by HIV-1 and HIV-2 taps a cullin5 ubiquitin ligase complex to mark the antiviral protein APOBEC3G for destruction. Viral Protein R of HIV-1 (Vpr) assembles with the CRL4 ubiquitin ligase complex to deplete uracil-N-glycosylase2 (UNG2). Covalent attachment of the ubiquitin-like protein side-chain NEDD8 functionally activates cullins which are common to all of these processes. RESULTS: The requirement for neddylation in HIV-1 and HIV-2 infectivity was tested in the presence of APOBEC3G and SAMHD1 respectively. Further the need for neddylation in HIV-1 Vpr-mediated depletion of UNG2 was probed. Treatment with MLN4924, an adenosine sulfamate analog which hinders the NEDD8 activating enzyme NAE1, blocked neddylation of cullin4A (CUL4A). The inhibitor hindered HIV-1 infection in the presence of APOBEC3G, even when Vif was expressed, and it stopped HIV-2 infection in the presence of SAMHD1 and Vpx. Consistent with these findings, MLN4924 prevented Vpx-mediated depletion of SAMHD1 in macrophages infected with Vpx-expressing HIV-2, as well as HIV-1 Vif-mediated destruction of APOBEC3G. It also stemmed Vpr-mediated UNG2 elimination from cells infected with HIV-1. CONCLUSIONS: Neddylation plays an important role in HIV-1 and HIV-2 infection. This observation is consistent with the essential parts that cullin-based ubiquitin ligases play in overcoming cellular anti-viral defenses. BioMed Central 2013-11-18 /pmc/articles/PMC3842660/ /pubmed/24245672 http://dx.doi.org/10.1186/1742-4690-10-138 Text en Copyright © 2013 Nekorchuk et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Nekorchuk, Michael D Sharifi, Hamayun J Furuya, Andrea KM Jellinger, Robert de Noronha, Carlos MC HIV relies on neddylation for ubiquitin ligase-mediated functions |
title | HIV relies on neddylation for ubiquitin ligase-mediated functions |
title_full | HIV relies on neddylation for ubiquitin ligase-mediated functions |
title_fullStr | HIV relies on neddylation for ubiquitin ligase-mediated functions |
title_full_unstemmed | HIV relies on neddylation for ubiquitin ligase-mediated functions |
title_short | HIV relies on neddylation for ubiquitin ligase-mediated functions |
title_sort | hiv relies on neddylation for ubiquitin ligase-mediated functions |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842660/ https://www.ncbi.nlm.nih.gov/pubmed/24245672 http://dx.doi.org/10.1186/1742-4690-10-138 |
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