Cryo-EM micrographs of APOBEC3G bound to HIV-1 Vif in comblex with CBF-beta and CUL5 E3 ligase
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ABSTRACT:
SUBMITTER: Fumiaki Ito
PROVIDER: EMPIAR-11339 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
Structural basis for HIV-1 antagonism of host APOBEC3G via Cullin E3 ligase.
Ito Fumiaki F Alvarez-Cabrera Ana L AL Liu Shiheng S Yang Hanjing H Shiriaeva Anna A Zhou Z Hong ZH Chen Xiaojiang S XS
Science advances 20230104 1
Human APOBEC3G (A3G) is a virus restriction factor that inhibits HIV-1 replication and triggers lethal hypermutation on viral reverse transcripts. HIV-1 viral infectivity factor (Vif) breaches this host A3G immunity by hijacking a cellular E3 ubiquitin ligase complex to target A3G for ubiquitination and degradation. The molecular mechanism of A3G targeting by Vif-E3 ligase is unknown, limiting the antiviral efforts targeting this host-pathogen interaction crucial for HIV-1 infection. Here, we re ...[more]
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Project description:Restriction factors, such as the retroviral complementary DNA deaminase APOBEC3G, are cellular proteins that dominantly block virus replication. The AIDS virus, human immunodeficiency virus type 1 (HIV-1), produces the accessory factor Vif, which counteracts the host's antiviral defence by hijacking a ubiquitin ligase complex, containing CUL5, ELOC, ELOB and a RING-box protein, and targeting APOBEC3G for degradation. Here we reveal, using an affinity tag/purification mass spectrometry approach, that Vif additionally recruits the transcription cofactor CBF-? to this ubiquitin ligase complex. CBF-?, which normally functions in concert with RUNX DNA binding proteins, allows the reconstitution of a recombinant six-protein assembly that elicits specific polyubiquitination activity with APOBEC3G, but not the related deaminase APOBEC3A. Using RNA knockdown and genetic complementation studies, we also demonstrate that CBF-? is required for Vif-mediated degradation of APOBEC3G and therefore for preserving HIV-1 infectivity. Finally, simian immunodeficiency virus (SIV) Vif also binds to and requires CBF-? to degrade rhesus macaque APOBEC3G, indicating functional conservation. Methods of disrupting the CBF-?-Vif interaction might enable HIV-1 restriction and provide a supplement to current antiviral therapies that primarily target viral proteins.
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