CUL4B
Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome.[5][6] CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.
Structure
[edit]Human CUL4B is 913 amino acids long and shares a high degree of sequence identity (84%) with CUL4A with the exception of its unique N-terminal region.[7] The extreme N-terminus of CUL4B is disordered and, currently, it is unclear what structural and functional qualities it possesses. CUL4B binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). This interaction is crucial for the recruitment of substrates to the ubiquitin ligase complex. At the C-terminal end, CUL4B interacts with the RBX1/ROC1 protein via its RING domain. RBX1 is a core component of Cullin-RING ubiquitin ligase (CRL) complexes and functions to recruit E2 ubiquitin conjugating enzymes. Therefore, the C-terminus of CUL4B - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4B complexes. CUL4B is also modified by covalent attachment of a NEDD8 molecule at a highly conserved lysine residue in the C-terminal region. This modification appears to induce conformational changes which promotes flexibility in the RING domain of cullin proteins and enhanced ubiquitin ligase activity.[8]
Functions
[edit]Cell cycle regulation and chromatin remodeling
[edit]CUL4B-based E3 ubiquitin ligase complexes often demonstrate overlapping activity with CUL4A-based complexes. Both CRL4 complexes utilize Cdt2 and the DNA processivity factor PCNA to induce the ubiquitination and degradation of replication licensing factor Cdt1 and cyclin-dependent kinase inhibitor p21 in a proteasome-dependent manner.[9][10] CRL4Cdt2 also degrades PCNA-bound PR-Set7/SET8, which is a histone 4 methyltransferase, and the p12 subunit of DNA polymerase δ, which is crucial for DNA replication.[11][12] As a result, CRL4 complexes are able to control the onset of DNA replication, chromatin remodeling and progression through the cell cycle.
Mammalian embryonic development
[edit]Loss of Cul4b in mice causes embryonic lethality and defects in placental development. The extra-embryonic tissue of these developing mice also showed increased rates of apoptosis and a decrease in cell proliferation. When Cul4b deletion was limited to the epiblast (only in Sox2-expressing tissue), it was possible to generate living mice.[13]
Neurological development
[edit]Mice that do not express CUL4B in epiblast tissue demonstrate normal brain morphology but decrease number of parvalbumin (PV)-positive GABAergic interneurons - particularly in the dentate gyrus.[14] In these mice, certain dendritic features of hippocampal neurons were also affected by Cul4b loss, which may explain the observed increases in epileptic susceptibility and spatial learning defects. These phenotypes resembled features seen in patients with X-linked intellectual disability (see below).
Clinical significance
[edit]X-linked intellectual disability
[edit]Loss-of-function CUL4B mutation events have been discovered in numerous patients with X-linked intellectual disability, which is characterized by aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus and tremor.[15][16][17] CUL4B mutations have also been associated with malformations of cortical development.[18]
Viral pathogenesis
[edit]After HIV infects a cell, the virus "hijacks" either the CUL4B-DDB1 complex or the CUL4A-DDB1 complex via the same mechanism. Essentially, HIV proteins such as Vpr and Vpx bind to VPRBP (a DDB1-binding substrate receptor protein) and induce the ubiquitination and degradation of SAMHD1 and UNG2 to promote viral replication.[19] These proteins are not degraded by CRL4 complexes in the absence of virus.
Cancer
[edit]According to data from The Cancer Genome Atlas, CUL4B is mutated in 21% of pancreatic carcinomas with a recurring truncating mutation at amino acid 143. CUL4B is also mutated or amplified in 3-5% of lung cancers. The significance of these observed mutations has not been determined.
Thalidomide treatment
[edit]In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.[20] Thalidomide and other derivatives such as pomalidomide and lenalidomide are known as immunomodulatory drugs (or IMiDs) and have been investigated as therapeutic agents for autoimmune diseases and several cancers - particularly myelomas. Recent reports show that IMiDs bind to CRL4CRBN and promote the degradation of IKZN1 and IKZN3 transcription factors, which are not normally targeted by CRL4 complexes.[21][22]
Interactions and substrates
[edit]Human CUL4B forms direct interactions with:
Human CUL4B-DDB1-RBX1 complexes promote the ubiquitination of:
- Cdt1[9][27]
- p21[10][28]
- PR-Set7/SET8[11]
- p12 subunit of DNA polymerase δ[12]
- SAMHD1†[19]
- UNG2†[19]
- IKZF1§[21][22]
- IKZF3§[21][22]
†protein is a CRL4 substrate only when directed by viral proteins
§protein is a CRL4 substrate only when directed by IMiDs
Notes
[edit]
 | The 2015 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Jeffrey Hannah; Pengbo Zhou (15 November 2015). "Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B". Gene. Gene Wiki Review Series. 573 (1): 33–45. doi:10.1016/J.GENE.2015.08.064. ISSN 0378-1119. PMC 5110433. PMID 26344709. Wikidata Q28086765. |
References
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- ^ Londin ER, Adijanto J, Philp N, Novelli A, Vitale E, Perria C, Serra G, Alesi V, Surrey S, Fortina P (2014). "Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability". Am. J. Med. Genet. A. 164A (9): 2294–9. doi:10.1002/ajmg.a.36629. PMC 4404493. PMID 24898194.
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- ^ Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M (Feb 2007). "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor". American Journal of Human Genetics. 80 (2): 345–52. doi:10.1086/511134. PMC 1785336. PMID 17236139.
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- ^ Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (Mar 2010). "Identification of a primary target of thalidomide teratogenicity". Science. 327 (5971): 1345––50. Bibcode:2010Sci...327.1345I. doi:10.1126/science.1177319. PMID 20223979. S2CID 17575104.
- ^ a b c Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG (Jan 2014). "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins". Science. 343 (6168): 305–9. Bibcode:2014Sci...343..305L. doi:10.1126/science.1244917. PMC 4070318. PMID 24292623.
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- ^ Ohta T, Michel JJ, Schottelius AJ, Xiong Y (Apr 1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Molecular Cell. 3 (4): 535–41. doi:10.1016/s1097-2765(00)80482-7. PMID 10230407. S2CID 19371828.
- ^ Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982.
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- ^ Chew EH, Hagen T (Jun 2007). "Substrate-mediated regulation of cullin neddylation". The Journal of Biological Chemistry. 282 (23): 17032–40. doi:10.1074/jbc.M701153200. PMID 17439941.
- ^ Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T (Mar 2006). "Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis". The EMBO Journal. 25 (5): 1126–36. doi:10.1038/sj.emboj.7601002. PMC 1409712. PMID 16482215.
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External links
[edit]- Human CUL4B genome location and CUL4B gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: Q13620 (Human Cullin-4B) at the PDBe-KB.
Further reading
[edit]- Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (2003). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Res. 9 (3): 99–106. doi:10.1093/dnares/9.3.99. PMID 12168954.
- Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Res. 5 (3): 169–76. doi:10.1093/dnares/5.3.169. PMID 9734811.
- Wada H, Yeh ET, Kamitani T (1999). "Identification of NEDD8-conjugation site in human cullin-2". Biochem. Biophys. Res. Commun. 257 (1): 100–5. doi:10.1006/bbrc.1999.0339. PMID 10092517.
- Ohta T, Michel JJ, Schottelius AJ, Xiong Y (1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Mol. Cell. 3 (4): 535–41. doi:10.1016/S1097-2765(00)80482-7. PMID 10230407. S2CID 19371828.
- Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K (2000). "Covalent modification of all members of human cullin family proteins by NEDD8". Oncogene. 18 (48): 6829–34. doi:10.1038/sj.onc.1203093. PMID 10597293.
- Jones EA, Clement-Jones M, Wilson DI (2000). "JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype". J. Med. Genet. 37 (9): 658–62. doi:10.1136/jmg.37.9.658. PMC 1734694. PMID 10978356.
- Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H (2003). "CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex". Mol. Cell. 10 (6): 1519–26. doi:10.1016/S1097-2765(02)00784-0. PMID 12504026.
- Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982.
- Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H (2004). "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint". Nat. Cell Biol. 5 (11): 1008–15. doi:10.1038/ncb1061. PMID 14578910. S2CID 26070877.
- Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
- Higa LA, Yang X, Zheng J, Banks D, Wu M, Ghosh P, Sun H, Zhang H (2006). "Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation". Cell Cycle. 5 (1): 71–7. doi:10.4161/cc.5.1.2266. PMID 16322693.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Senga T, Sivaprasad U, Zhu W, Park JH, Arias EE, Walter JC, Dutta A (2006). "PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination". J. Biol. Chem. 281 (10): 6246–52. doi:10.1074/jbc.M512705200. PMID 16407252.
- Li T, Santockyte R, Shen RF, Tekle E, Wang G, Yang DC, Chock PB (2006). "A general approach for investigating enzymatic pathways and substrates for ubiquitin-like modifiers". Arch. Biochem. Biophys. 453 (1): 70–4. doi:10.1016/j.abb.2006.03.002. PMID 16620772.
- Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y (2006). "Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage". Mol. Cell. 22 (3): 383–94. doi:10.1016/j.molcel.2006.03.035. PMID 16678110. S2CID 25677159.
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