TY - JOUR
T1 - T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction
AU - Zhang, Wenyan
AU - Du, Juan
AU - Evans, Sean L.
AU - Yu, Yunkai
AU - Yu, Xiao Fang
N1 - Funding Information:
Acknowledgements We thank K. Strebel, A. Friedman, N. Speck, D. Yue, R. Siliciano, M. Malim, R. Harris, T. Inoue and D. Gabuzda for critical reagents; T. Wang, K. Zhao, X. Zhou and A. Zhen for technical assistance; R. Markham, J. Margolick and J. Bream for thoughtful discussions; and D. McClellan for editorial assistance. We also wish to thank staff within the Mass Spectrometry Core and the Institute for Basic Biomedical Sciences Microscope Facility at Johns Hopkins School of Medicine for their technical assistance. The following reagents were obtained through the AIDS Research and Reference Reagents Program, Division of AIDS, NIAID, NIH: monoclonal antibodies against HIV-1 p24 (B. Chesebro and H. Chen), pNL4-3 (M. Martin), pcDNA-hVif (S. Bour and K. Strebel), antiserum to HIV-1 Vif (D. Gabuzda) and MAGI-CCR5 cells (J. Overbaugh). This work was supported in part by funding from the Chinese Ministry of Science and Technology (2012CB911100) and Chinese Ministry of Education (IRT1016), the Key Laboratory of Molecular Virology, Jilin Province (20102209), China, and a grant (2R56AI62644-6) from the NIAID.
PY - 2012/1/19
Y1 - 2012/1/19
N2 - The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1). HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C, which promotes the polyubiquitination and degradation of APOBEC3 substrates. Here we demonstrate in human T cells that core binding factor β (CBF-β) is a key regulator of the evasion of HIV-1 from the host defence mediated by APOBEC3. CBF-β, the non-DNA-binding subunit of a heterodimeric transcription factor, regulates the folding and DNA-binding activity of partner RUNX family proteins, which have important roles in the development and differentiation of diverse cell types, including T lymphocytes. In our study, knockdown of endogenous CBF-β blocked Vif-induced APOBEC3G polyubiquitination and degradation. CBF-β was not required for the interaction between Vif and APOBEC3G, yet was essential for the assembly of the Vif-CUL5 E3-ubiquitin-ligase complex. CBF-β proved to be a unique regulator of primate lentiviral Vif and not a general component of the CUL5 E3 ubiquitin ligase. We show that Vif and CBF-β physically interact, and that the amino-terminal region of Vif is required for this interaction. Furthermore, interactions with Vif required regions in CBF-β that are not involved in RUNX protein binding. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.
AB - The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1). HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C, which promotes the polyubiquitination and degradation of APOBEC3 substrates. Here we demonstrate in human T cells that core binding factor β (CBF-β) is a key regulator of the evasion of HIV-1 from the host defence mediated by APOBEC3. CBF-β, the non-DNA-binding subunit of a heterodimeric transcription factor, regulates the folding and DNA-binding activity of partner RUNX family proteins, which have important roles in the development and differentiation of diverse cell types, including T lymphocytes. In our study, knockdown of endogenous CBF-β blocked Vif-induced APOBEC3G polyubiquitination and degradation. CBF-β was not required for the interaction between Vif and APOBEC3G, yet was essential for the assembly of the Vif-CUL5 E3-ubiquitin-ligase complex. CBF-β proved to be a unique regulator of primate lentiviral Vif and not a general component of the CUL5 E3 ubiquitin ligase. We show that Vif and CBF-β physically interact, and that the amino-terminal region of Vif is required for this interaction. Furthermore, interactions with Vif required regions in CBF-β that are not involved in RUNX protein binding. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.
UR - http://www.scopus.com/inward/record.url?scp=84856014513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856014513&partnerID=8YFLogxK
U2 - 10.1038/nature10718
DO - 10.1038/nature10718
M3 - Article
C2 - 22190036
AN - SCOPUS:84856014513
SN - 0028-0836
VL - 481
SP - 376
EP - 379
JO - Nature
JF - Nature
IS - 7381
ER -