CUL4B

Cullin 4B
PDB CUL4B fragment rendering based on 2do7.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2DO7​, 4A0C​, 4A0L​, 4A64​
Identifiers
Symbols	CUL4B ; CUL-4B; MRXHF2; MRXS15; MRXSC; SFM2
External IDs	OMIM: 300304 MGI: 1919834 HomoloGene: 2660 GeneCards: CUL4B Gene
Gene ontology Molecular function • damaged DNA binding • protein binding • ubiquitin protein ligase binding • ubiquitin protein ligase activity Cellular component • nucleoplasm • cytoplasm • cytosol • plasma membrane • Cul4B-RING E3 ubiquitin ligase complex • extracellular exosome Biological process • DNA repair • cell cycle • translesion synthesis • neuron projection development • histone H2A monoubiquitination • DNA damage response, detection of DNA damage • protein ubiquitination involved in ubiquitin-dependent protein catabolic process • positive regulation of protein catabolic process • UV-damage excision repair • positive regulation of G1/S transition of mitotic cell cycle Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8450	72584
Ensembl	ENSG00000158290	ENSMUSG00000031095
UniProt	Q13620	A2A432
RefSeq (mRNA)	NM_001079872	NM_001110142
RefSeq (protein)	NP_001073341	NP_001103612
Location (UCSC)	Chr X: 120.52 – 120.58 Mb	Chr X: 38.53 – 38.58 Mb
PubMed search

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome.^[1][2] 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

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.^[3] 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.^[4]

Functions

Cell cycle regulation and chromatin remodeling

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.^[5][6] CRL4^Cdt2 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.^[7][8] 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

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.^[9]

Neurological development

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.^[10] In these mice, certain dendritic features of hippocampal neurons were also affected by Cul4b loss, which may explain the observed increases in epilectic susceptibility and spatial learning defects. These phenotypes resembled features seen in patients with X-linked intellectual disability (see below).

Clinical significance

X-linked intellectual disability

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.^[11][12][13] CUL4B mutations have also been associated with malformations of cortical development.^[14]

Viral pathogenesis

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.^[15] These proteins are not degraded by CRL4 complexes in the absence of virus.

Cancer

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

In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.^[16] 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 CRL4^CRBN and promote the degradation of IKZN1 and IKZN3 transcription factors, which are not normally targeted by CRL4 complexes.^[17][18]

Interactions and substrates

Human CUL4B forms direct interactions with:

• RBX1^[19]
• CAND1^[20]
• DDB1^[21] and
• the COP9 signalosome^[22]

Human CUL4B-DDB1-RBX1 complexes promote the ubiquitination of:

• Cdt1^[5][23]
• p21^[6][24]
• PR-Set7/SET8^[7]
• p12 subunit of DNA polymerase δ^[8]
• SAMHD1†^[15]
• UNG2†^[15]
• IKZF1^§[17][18]
• IKZF3^§[17][18]

^†protein is a CRL4 substrate only when directed by viral proteins
^§protein is a CRL4 substrate only when directed by IMiDs

References

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2. "Entrez Gene: CUL4B cullin 4B".
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5. Hu J, Xiong Y (Feb 2006). "An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage". The Journal of Biological Chemistry 281 (7): 3753–6. doi:10.1074/jbc.C500464200. PMID 16407242.
6. Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T (Oct 2008). "CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation". The Journal of Biological Chemistry 283 (43): 29045–52. doi:10.1074/jbc.M806045200. PMC 2662008. PMID 18703516.
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8. Zhang S, Zhao H, Darzynkiewicz Z, Zhou P, Zhang Z, Lee EY, Lee MY (Oct 2013). "A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase δ in response to DNA damage and during the S phase". The Journal of Biological Chemistry 288 (41): 29550–61. doi:10.1074/jbc.M113.490466. PMID 23913683.
9. Liu L, Yin Y, Li Y, Prevedel L, Lacy EH, Ma L, Zhou P (Aug 2012). "Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis". Cell Research 22 (8): 1258–69. doi:10.1038/cr.2012.48. PMID 22453236.
10. Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ, Lin SW (Oct 2012). "Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation". Human Molecular Genetics 21 (19): 4270–85. doi:10.1093/hmg/dds261. PMID 22763239.
11. 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. PMID 24898194.
12. Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y (Mar 2007). "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation". American Journal of Human Genetics 80 (3): 561–6. doi:10.1086/512489. PMID 17273978.
13. 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. PMID 17236139.
14. Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, Vissers LE, Gilissen C, Tzschach A, Busche A, Müsebeck J, Rump P, Mathijssen IB, Avela K, Somer M, Doagu F, Philips AK, Rauch A, Baumer A, Voesenek K, Poirier K, Vigneron J, Amram D, Odent S, Nawara M, Obersztyn E, Lenart J, Charzewska A, Lebrun N, Fischer U, Nillesen WM, Yntema HG, Järvelä I, Ropers HH, de Vries BB, Brunner HG, van Bokhoven H, Raymond FL, Willemsen MA, Chelly J, Xiong Y, Barkovich AJ, Kalscheuer VM, Kleefstra T, de Brouwer AP (Jan 2015). "Variants in CUL4B are associated with cerebral malformations". Human Mutation 36 (1): 106–17. doi:10.1002/humu.22718. PMID 25385192.
15. Sharifi HJ, Furuya AK, Jellinger RM, Nekorchuk MD, de Noronha CM (Jun 2014). "Cullin4A and cullin4B are interchangeable for HIV Vpr and Vpx action through the CRL4 ubiquitin ligase complex". Journal of Virology 88 (12): 6944–58. doi:10.1128/JVI.00241-14. PMID 24719410.
16. 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. doi:10.1126/science.1177319. PMID 20223979.
17. 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. doi:10.1126/science.1244917. PMID 24292623.
18. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL (Jan 2014). "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells". Science 343 (6168): 301–5. doi:10.1126/science.1244851. PMID 24292625.
19. 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.
20. 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.
21. Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapić-Otrin V (Jul 2008). "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A". Cancer Research 68 (13): 5014–22. doi:10.1158/0008-5472.CAN-07-6162. PMID 18593899.
22. 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.
23. 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. PMID 16482215.
24. Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (Sep 2008). "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex". Genes & Development 22 (18): 2496–506. doi:10.1101/gad.1676108. PMC 2546691. PMID 18794347.

Further reading

• 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.
• 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.
• 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. 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.