Abstract
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 F E3 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 F E3 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.
Highlights
Tracy Augustine‡, Priyanka Chaudhary‡, Kailash Gupta‡, Sehbanul Islam‡, Payel Ghosh§, Manas Kumar Santra‡, and Debashis Mitra‡1 From the ‡National Centre for Cell Science, Pune, Maharashtra 411007, India and the §Bioinformatics Centre, Savitribai Phule Pune University, Pune, Maharashtra 411007, India
Our results demonstrate that cyclin F is a novel F-box protein that functions as an intrinsic cellular regulator of HIV-1 viral infectivity factor (Vif) and has a negative regulatory effect on the maintenance of viral infectivity by restoring APOBEC3G expression
We have identified cyclin F as a significantly down-regulated gene in HIV-1-infected CD4ϩ T cells
Summary
Viral infectivity factor; CDK, cyclin-dependent kinase; PBMC, peripheral blood mononuclear cell; m.o.i., multiplicity of infection; hpi, hours post-infection; co-IP, co-immunoprecipitation; A3G, APOBEC3G; PHA, phytohemagglutinin; PDB, Protein Data Bank. Other cell cycle-associated genes identified as playing significant role in HIV-1 infection include p21/ CDKN1A, which acts as an intrinsic inhibitor of HIV-1 reverse transcription in CD4ϩ T cells of elite controllers [22]; and cyclin A2 [23] and cyclin L2 [24], which are exploited by HIV-1 to evade the restriction function of SAMHD1 in different cell types, thereby enabling the virus to replicate efficiently. Cyclin F has been shown to suppress B-Myb activity to ensure G2 checkpoint control in response to IR-induced DNA damage [33] These cellular regulatory functions mediated by cyclin F have enabled researchers to consider cyclin F as a potential molecular target in cancer therapeutics. Subsequent analysis elucidated a novel physical interaction between cyclin F and viral protein Vif by which cyclin F regulates Vif expression in a proteasome-dependent manner, correlating with a direct implication of HIV-1 progeny virion infectivity
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