| Structural highlights
Disease
[PEBB_HUMAN] Note=A chromosomal aberration involving CBFB is associated with acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein that consists of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11.
Function
[ABC3F_HUMAN] DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits antiviral activity against vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity also against hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV) and may inhibit the mobility of LTR and non-LTR retrotransposons. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [VIF_HV1N5] Counteracts the innate antiviral activity of human APOBEC3F and APOBEC3G. Forms a complex with host APOBEC3F and APOBEC3G thus preventing the entry of these lethally hypermutating enzymes into progeny virions. Recruits an active E3 ubiquitin ligase complex composed of elongin BC, CUL5, and RBX2 to induce polyubiquitination of APOBEC3G and APOBEC3F. In turn, they are directed to the 26S proteasome for degradation. Vif interaction with APOBEC3G also blocks its cytidine deaminase activity in a proteasome-independent manner, suggesting a dual inhibitory mechanism. May interact directly with APOBEC3G mRNA in order to inhibit its translation. Seems to play a role in viral morphology by affecting the stability of the viral nucleoprotein core. Finally, Vif also contributes to the G2 cell cycle arrest observed in HIV infected cells (By similarity).[14] [15] [PEBB_HUMAN] CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. CBFB enhances DNA binding by RUNX1.
Publication Abstract from PubMed
HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of human immunodeficiency virus type 1 (HIV-1) replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and the cellular cofactor core-binding factor beta (CBFbeta) at 3.9-A resolution. The structure shows that Vif and CBFbeta form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFbeta beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F.
Structural basis of antagonism of human APOBEC3F by HIV-1 Vif.,Hu Y, Desimmie BA, Nguyen HC, Ziegler SJ, Cheng TC, Chen J, Wang J, Wang H, Zhang K, Pathak VK, Xiong Y Nat Struct Mol Biol. 2019 Dec;26(12):1176-1183. doi: 10.1038/s41594-019-0343-6., Epub 2019 Dec 2. PMID:31792451[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wiegand HL, Doehle BP, Bogerd HP, Cullen BR. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. EMBO J. 2004 Jun 16;23(12):2451-8. Epub 2004 May 20. PMID:15152192 doi:10.1038/sj.emboj.7600246
- ↑ Chen H, Lilley CE, Yu Q, Lee DV, Chou J, Narvaiza I, Landau NR, Weitzman MD. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr Biol. 2006 Mar 7;16(5):480-5. PMID:16527742 doi:10.1016/j.cub.2006.01.031
- ↑ Delebecque F, Suspene R, Calattini S, Casartelli N, Saib A, Froment A, Wain-Hobson S, Gessain A, Vartanian JP, Schwartz O. Restriction of foamy viruses by APOBEC cytidine deaminases. J Virol. 2006 Jan;80(2):605-14. PMID:16378963 doi:10.1128/JVI.80.2.605-614.2006
- ↑ Zielonka J, Bravo IG, Marino D, Conrad E, Perkovic M, Battenberg M, Cichutek K, Munk C. Restriction of equine infectious anemia virus by equine APOBEC3 cytidine deaminases. J Virol. 2009 Aug;83(15):7547-59. doi: 10.1128/JVI.00015-09. Epub 2009 May 20. PMID:19458006 doi:10.1128/JVI.00015-09
- ↑ Mbisa JL, Bu W, Pathak VK. APOBEC3F and APOBEC3G inhibit HIV-1 DNA integration by different mechanisms. J Virol. 2010 May;84(10):5250-9. doi: 10.1128/JVI.02358-09. Epub 2010 Mar 10. PMID:20219927 doi:10.1128/JVI.02358-09
- ↑ Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu WS, Pathak VK. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J Virol. 2010 Jun;84(11):5719-29. doi: 10.1128/JVI.00134-10. Epub 2010 Mar 24. PMID:20335265 doi:10.1128/JVI.00134-10
- ↑ Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol. 2010 Feb;17(2):222-9. doi: 10.1038/nsmb.1744. Epub 2010 Jan , 10. PMID:20062055 doi:10.1038/nsmb.1744
- ↑ Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr, 14. PMID:21496894 doi:10.1016/j.cell.2011.03.022
- ↑ Hultquist JF, Lengyel JA, Refsland EW, LaRue RS, Lackey L, Brown WL, Harris RS. Human and rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H demonstrate a conserved capacity to restrict Vif-deficient HIV-1. J Virol. 2011 Nov;85(21):11220-34. doi: 10.1128/JVI.05238-11. Epub 2011 Aug 10. PMID:21835787 doi:10.1128/JVI.05238-11
- ↑ Phalora PK, Sherer NM, Wolinsky SM, Swanson CM, Malim MH. HIV-1 replication and APOBEC3 antiviral activity are not regulated by P bodies. J Virol. 2012 Nov;86(21):11712-24. doi: 10.1128/JVI.00595-12. Epub 2012 Aug 22. PMID:22915799 doi:10.1128/JVI.00595-12
- ↑ Refsland EW, Hultquist JF, Harris RS. Endogenous origins of HIV-1 G-to-A hypermutation and restriction in the nonpermissive T cell line CEM2n. PLoS Pathog. 2012;8(7):e1002800. doi: 10.1371/journal.ppat.1002800. Epub 2012 Jul, 12. PMID:22807680 doi:10.1371/journal.ppat.1002800
- ↑ Chaipan C, Smith JL, Hu WS, Pathak VK. APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4+ T cells and macrophages. J Virol. 2013 Jan;87(1):444-53. doi: 10.1128/JVI.00676-12. Epub 2012 Oct 24. PMID:23097438 doi:10.1128/JVI.00676-12
- ↑ Gillick K, Pollpeter D, Phalora P, Kim EY, Wolinsky SM, Malim MH. Suppression of HIV-1 infection by APOBEC3 proteins in primary human CD4(+) T cells is associated with inhibition of processive reverse transcription as well as excessive cytidine deamination. J Virol. 2013 Feb;87(3):1508-17. doi: 10.1128/JVI.02587-12. Epub 2012 Nov 14. PMID:23152537 doi:10.1128/JVI.02587-12
- ↑ Hoglund S, Ohagen A, Lawrence K, Gabuzda D. Role of vif during packing of the core of HIV-1. Virology. 1994 Jun;201(2):349-55. PMID:8184544 doi:http://dx.doi.org/S0042-6822(84)71300-6
- ↑ Kao S, Khan MA, Miyagi E, Plishka R, Buckler-White A, Strebel K. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity. J Virol. 2003 Nov;77(21):11398-407. PMID:14557625
- ↑ Hu Y, Desimmie BA, Nguyen HC, Ziegler SJ, Cheng TC, Chen J, Wang J, Wang H, Zhang K, Pathak VK, Xiong Y. Structural basis of antagonism of human APOBEC3F by HIV-1 Vif. Nat Struct Mol Biol. 2019 Dec;26(12):1176-1183. doi: 10.1038/s41594-019-0343-6., Epub 2019 Dec 2. PMID:31792451 doi:http://dx.doi.org/10.1038/s41594-019-0343-6
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