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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 |
Sumario: | 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. |
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