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VPRBP

From Wikipedia, the free encyclopedia

DCAF1
Identifiers
AliasesDCAF1, VPRBP, Vpr (HIV-1) binding protein, DDB1 and CUL4 associated factor 1, RIP
External IDsOMIM: 617259; MGI: 2445220; HomoloGene: 8805; GeneCards: DCAF1; OMA:DCAF1 - orthologs
Available structures
PDBOrtholog search: PDBe RCSB
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
2.7.11.1↗↗↗↗
Orthologs
SpeciesHumanMouse
Entrez

9730

321006

Ensembl

ENSG00000145041

ENSMUSG00000040325

UniProt

Q9Y4B6

Q80TR8

RefSeq (mRNA)

NM_001015507
NM_001373930
NM_001373931

RefSeq (protein)

NP_001015507
NP_001360859
NP_001360860

Location (UCSC)Chr 3: 51.4 – 51.5 MbChr 9: 106.7 – 106.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

DDB1 and CUL4 associated factor 1 (DCAF1), originally known as Vpr Binding Protein (VprBP), is an adapter protein for the E3 Ubiquitin Ligase CRL4.[5] DCAF1 in humans is encoded by the VPRBP gene.[6][7] Both names originate from research on HIV: DCAF1 was named for its first discovered role as the primary target of HIV accessory protein Vpr.[5] Subsequent studies identified its role in the DDB1-CUL4 axis. Targeting of DDB1 and CUL4 through DCAF1 by Vpr disrupted cell cycle entry of infected cells, thereby promoting HIV viral replication.[8][9][10] DCAF1 has been implicated in the development of various cancers.[11]

Structure

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DCAF1 is 1507 amino acids (aa) long. It contains the following domains:[11]

  • Casein Kinase-like (141-500 aa)
  • Chromo-like (562-593 aa)
  • Armadillo (80-141, 500-562, 593-796 aa)
  • LisH (846-878 aa)
  • HLH-motif (1050-1079 aa)
  • H-box WD40 (1081-1388 aa)
  • Acidic (1397-1507 aa)

Here is a revised version with improved clarity, flow, and organization while retaining the Wikipedia markup and citations:

Function

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DCAF1 functions as a substrate receptor for the CRL4 (Roc-CUL4A-DDB1) ubiquitin ligase complex, directing the ubiquitination and degradation of a wide range of cellular and viral proteins.

One of its best-characterized substrates is the proto-oncoprotein Merlin. CRL4DCAF1-mediated degradation of Merlin reduces Rac1 and ERK1 signaling, two pathways that regulate cancer cell proliferation and motility.[12][13][14] Conversely, nuclear Merlin binds DCAF1 and inhibits CRL4DCAF1 activity, thereby suppressing oncogene expression.[15]

DCAF1 also regulates the tumor suppressor p53. USP2 stabilizes DCAF1, resulting in reduced p53 levels.[16] Knockdown studies have shown that DCAF1-mediated regulation of p53 contributes to cell-cycle entry but has little effect on overall cellular growth.[17] In addition, DCAF1 phosphorylates p53 at Ser367, promoting its ubiquitination and attenuating the DNA damage response.[18]

DCAF1 regulates gene expression by targeting histones H2A and H3 for modification.[19][20] It also promotes female fertility by activating TET genes in oocytes, thereby protecting female germ cell development.[21]

DCAF1 is exploited by several lentiviruses. The SIV accessory protein Vpx binds DCAF1 to promote the ubiquitination and degradation of the antiviral restriction factor SAMHD1.[22] Similarly, the HIV accessory protein Vpr co-opts DCAF1 to disrupt multiple cellular pathways, a process that contributes substantially, although is not essential, to viral replication.[23][24][25] In contrast, cellular miRNA-1237 suppresses DCAF1 expression in HIV-infected macrophages, thereby restricting viral replication.[26]

DCAF1 also regulates lipid metabolism by promoting the degradation of TR4 and TAK1, reducing fatty acid uptake and triglyceride synthesis and storage. This activity of the DCAF1-DDB1-CUL4B complex is inhibited by the metabolic regulator SIRT7, relieving repression of TR4 and TAK1.[27]

References

[edit]
  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145041 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040325 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Zhang S, Feng Y, Narayan O, Zhao LJ (January 2001). "Cytoplasmic retention of HIV-1 regulatory protein Vpr by protein-protein interaction with a novel human cytoplasmic protein VprBP". Gene. 263 (1–2): 131–140. doi:10.1016/S0378-1119(00)00583-7. PMID 11223251.
  6. ↑ Zhao LJ, Mukherjee S, Narayan O (June 1994). "Biochemical mechanism of HIV-I Vpr function. Specific interaction with a cellular protein". The Journal of Biological Chemistry. 269 (22): 15577–15582. doi:10.1016/S0021-9258(17)40719-8. PMID 8195203.
  7. ↑ "Entrez Gene: VPRBP Vpr (HIV-1) binding protein".
  8. ↑ Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, et al. (July 2007). "Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle". Proceedings of the National Academy of Sciences of the United States of America. 104 (28): 11778–11783. Bibcode:2007PNAS..10411778H. doi:10.1073/pnas.0702102104. PMC 1906728. PMID 17609381.
  9. ↑ Tan L, Ehrlich E, Yu XF (October 2007). "DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest". Journal of Virology. 81 (19): 10822–10830. doi:10.1128/JVI.01380-07. PMC 2045451. PMID 17626091.
  10. ↑ Wen X, Duus KM, Friedrich TD, de Noronha CM (September 2007). "The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor". The Journal of Biological Chemistry. 282 (37): 27046–27057. Bibcode:2007JBiCh.28227046W. doi:10.1074/jbc.M703955200. PMID 17620334.
  11. 1 2 Schabla NM, Mondal K, Swanson PC (September 2019). "DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor". Journal of Molecular Cell Biology. 11 (9): 725–735. doi:10.1093/jmcb/mjy085. PMC 6821201. PMID 30590706.
  12. ↑ Huang J, Chen J (July 2008). "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation". Oncogene. 27 (29): 4056–4064. doi:10.1038/onc.2008.44. PMID 18332868.
  13. ↑ Vial E, Sahai E, Marshall CJ (July 2003). "ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility". Cancer Cell. 4 (1): 67–79. doi:10.1016/S1535-6108(03)00162-4. PMID 12892714.
  14. ↑ Wang Z, Pedersen E, Basse A, Lefever T, Peyrollier K, Kapoor S, et al. (June 2010). "Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo". Oncogene. 29 (23): 3362–3373. doi:10.1038/onc.2010.95. PMID 20383193.
  15. ↑ Li W, Giancotti FG (November 2010). "Merlin's tumor suppression linked to inhibition of the E3 ubiquitin ligase CRL4 (DCAF1)". Cell Cycle. 9 (22). Georgetown, Tex.: 4433–4436. doi:10.4161/cc.9.22.13838. PMC 3048042. PMID 21084862.
  16. ↑ Yi J, Tavana O, Li H, Wang D, Baer RJ, Gu W (April 2023). "Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy". Nature Communications. 14 (1) 1941. Bibcode:2023NatCo..14.1941Y. doi:10.1038/s41467-023-37617-3. PMC 10079682. PMID 37024504.
  17. ↑ Guo Z, Kong Q, Liu C, Zhang S, Zou L, Yan F, et al. (January 2016). "DCAF1 controls T-cell function via p53-dependent and -independent mechanisms". Nature Communications. 7 (1) 10307. Bibcode:2016NatCo...710307G. doi:10.1038/ncomms10307. PMC 4728445. PMID 26728942.
  18. ↑ Ghate NB, Kim S, Mehmood R, Shin Y, Kim K, An W (April 2023). "VprBP/DCAF1 regulates p53 function and stability through site-specific phosphorylation". Oncogene. 42 (17): 1405–1416. doi:10.1038/s41388-023-02685-8. PMC 10121470. PMID 37041410.
  19. ↑ Kim K, Kim JM, Kim JS, Choi J, Lee YS, Neamati N, et al. (November 2013). "VprBP has intrinsic kinase activity targeting histone H2A and represses gene transcription". Molecular Cell. 52 (3): 459–467. doi:10.1016/j.molcel.2013.09.017. PMC 3851289. PMID 24140421.
  20. ↑ Kim K, Heo K, Choi J, Jackson S, Kim H, Xiong Y, et al. (February 2012). "Vpr-binding protein antagonizes p53-mediated transcription via direct interaction with H3 tail". Molecular and Cellular Biology. 32 (4): 783–796. doi:10.1128/MCB.06037-11. PMC 3272969. PMID 22184063.
  21. ↑ Yu C, Zhang YL, Pan WW, Li XM, Wang ZW, Ge ZJ, et al. (December 2013). "CRL4 complex regulates mammalian oocyte survival and reprogramming by activation of TET proteins". Science. 342 (6165). New York, N.Y.: 1518–1521. Bibcode:2013Sci...342.1518Y. doi:10.1126/science.1244587. PMID 24357321.
  22. ↑ Wei W, Guo H, Han X, Liu X, Zhou X, Zhang W, et al. (November 2012). "A novel DCAF1-binding motif required for Vpx-mediated degradation of nuclear SAMHD1 and Vpr-induced G2 arrest: Vpx-mediated DCAF1 binding and SAMHD1 degradation". Cellular Microbiology. 14 (11): 1745–1756. doi:10.1111/j.1462-5822.2012.01835.x. PMID 22776683.
  23. ↑ Lubow J, Collins KL (July 2020). "Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis". Viruses. 12 (8): 809. doi:10.3390/v12080809. PMC 7472745. PMID 32726944.
  24. ↑ Dobransky A, Root M, Hafner N, Marcum M, Sharifi HJ (August 2024). "CRL4-DCAF1 Ubiquitin Ligase Dependent Functions of HIV Viral Protein R and Viral Protein X". Viruses. 16 (8): 1313. doi:10.3390/v16081313. PMC 11360348. PMID 39205287.
  25. ↑ Kogan M, Rappaport J (April 2011). "HIV-1 accessory protein Vpr: relevance in the pathogenesis of HIV and potential for therapeutic intervention". Retrovirology. 8 (1) 25. doi:10.1186/1742-4690-8-25. PMC 3090340. PMID 21489275.
  26. ↑ Ma L, Shen CJ, Cohen ÉA, Xiong SD, Wang JH (2014). Yang R (ed.). "miRNA-1236 inhibits HIV-1 infection of monocytes by repressing translation of cellular factor VprBP". PLOS ONE. 9 (6) e99535. Bibcode:2014PLoSO...999535M. doi:10.1371/journal.pone.0099535. PMC 4059663. PMID 24932481.
  27. ↑ Yoshizawa T, Karim MF, Sato Y, Senokuchi T, Miyata K, Fukuda T, et al. (April 2014). "SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway". Cell Metabolism. 19 (4): 712–721. doi:10.1016/j.cmet.2014.03.006. PMID 24703702.

Further reading

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Retrieved from "https://en.wikipedia.org/w/index.php?title=VPRBP&oldid=1361627942"