Cyclin F/FBXO1 Interacts with HIV-1 Viral Infectivity Factor (Vif) and Restricts Progeny Virion Infectivity by Ubiquitination and Proteasomal Degradation of Vif Protein through SCFcyclin FE3 Ligase Machinery.
Cyclin F protein, also known as FBXO1, is the largest among all cyclins and oscillates in the cell cycle like other cyclins. Apart from being a G2/M cyclin, cyclin F functions as the substrate-binding subunit of SCFcyclin FE3 ubiquitin ligase. In a gene expression analysis performed to identify novel gene modulations associated with cell cycle dysregulation during HIV-1 infection in CD4+T cells, we observed down-regulation of the cyclin F gene (CCNF). Later, using gene overexpression and knockdown studies, we identified cyclin F as negatively influencing HIV-1 viral infectivity without any significant impact on virus production. Subsequently, we found that cyclin F negatively regulates the expression of viral protein Vif (viral infectivity factor) at the protein level. We also identified a novel host-pathogen interaction between cyclin F and Vif protein in T cells during HIV-1 infection. Mutational analysis of a cyclin F-specific amino acid motif in the C-terminal region of Vif indicated rescue of the protein from cyclin F-mediated down-regulation. Subsequently, we showed that Vif is a novel substrate of the SCFcyclin FE3 ligase, where cyclin F mediates the ubiquitination and proteasomal degradation of Vif through physical interaction. Finally, we showed that cyclin F augments APOBEC3G expression through degradation of Vif to regulate infectivity of progeny virions. Taken together, our results demonstrate that cyclin F is a novel F-box protein that functions as an intrinsic cellular regulator of HIV-1 Vif and has a negative regulatory effect on the maintenance of viral infectivity by restoring APOBEC3G expression.
From the National Centre for Cell Science, Pune, Maharashtra 411007, India and.
Tracy
T
Augustine
From the National Centre for Cell Science, Pune, Maharashtra 411007, India and.
Priyanka
P
Chaudhary
From the National Centre for Cell Science, Pune, Maharashtra 411007, India and.
Kailash
K
Gupta
From the National Centre for Cell Science, Pune, Maharashtra 411007, India and.
Sehbanul
S
Islam
the Bioinformatics Centre, Savitribai Phule Pune University, Pune, Maharashtra 411007, India.
Payel
P
Ghosh
From the National Centre for Cell Science, Pune, Maharashtra 411007, India and.
Manas Kumar
MK
Santra
From the National Centre for Cell Science, Pune, Maharashtra 411007, India and dmitra@nccs.res.in dmitra01@yahoo.co.in.
Debashis
D
Mitra
D000071480:APOBEC-3G Deaminase / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes; D002478:Cells, Cultured; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044783:F-Box Proteins; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014771:Virion / Q000472:pathogenicity*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
C503669:CCNF protein, human; D016213:Cyclins; D044783:F-Box Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human
APOBEC3G; E3 ubiquitin ligase; F-box protein; Vif; Virion infectivity; cyclin F; host-pathogen interaction; human immunodeficiency virus (HIV); protein degradation; ubiquitylation (ubiquitination)