CUL3 explained

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.^{[1] [2] [3]}

Cullin 3 protein belongs to the family of cullins which in mammals contains eight proteins (Cullin 1, Cullin 2, Cullin 3, Cullin 4A, Cullin 4B, Cullin 5, Cullin 7 and Cullin 9).^[4] Cullin proteins are an evolutionarily conserved family of proteins throughout yeast, plants and mammals.^[5]

Protein function

Cullin 3 is a component of Cullin-RING E3 ubiquitin ligases complexes (CRLs) which are involved in protein ubiquitylation and represent a part of ubiquitin–proteasome system (UPS). Added ubiquitin moieties to the lysine residue by CRLs then target the protein for the proteasomal degradation.^[6] Cullin-RING E3 ubiquitin ligases are involved in many cellular processes responsible for cell cycle regulation, stress response, protein trafficking, signal transduction, DNA replication, transcription, protein quality control, circadian clock and development.^{[7] [8]}

Deletion of CUL3 gene in mice causes embryonic lethality.^[9]

Cullin 3-RING E3 ubiquitin ligases

Cullin 3-RING complex consists of Cullin 3 protein, RING-box protein 1 (RBX1), which recruits the ubiquitin-conjugating enzyme (E2), and a Bric-a-brac/Tramtrack/Broad (BTB) protein, a substrate recognition subunit. Cullin 3 protein is a core scaffold protein coordinating other components of the CRL complex.^[10] Cullin 3-RING complexes can also dimerise via their BTB domains which lead to creation of two substrate receptors and two catalytic RING domains.^[11]

Activation of the complex is regulated by the attachment of the ubiquitin-like protein NEDD8 to a conserved Lys residue in the cullin-homology domain, the process called neddylation.^[12] Deneddylation is conducted by an eight-subunit CSN complex which mediates the cleavage of the isopeptidic bond between NEDD8 and cullin protein.^[13] Another protein that interacts with cullin is CAND1 which binds to deneddylated form of cullin protein and disrupts the interaction between cullin and other subunits of the complex leading to inhibition of the E3 ubiquitin ligase activity.^[14] Therefore, dynamic neddylation and deneddylation of cullin is important for regulation of CRL complex activity.^[15]

Clinical significance

Familial hyperkalemic hypertension

Mutations in CUL3 gene are associated with Familial hyperkalemic hypertension disease. CRL complex containing Cullin 3 controls the activity of Na⁺ Cl⁻ cotransporter (NCC) in the kidney by regulating the proteasomal degradation of With-no-lysine [K] kinases WNK1 and WNK4. It was shown that mutations in CUL3 gene lead to WNKs accumulation.^[16] The abundance of these kinases leads to increased phosphorylation of NCC and its activation. As a consequence, Na⁺ reabsorption is increasing resulting in high blood pressure.^[17]

Neurodevelopmental Disorders

Cullin 3 is heavily involved in the regulation of the central nervous system. Cullin 3 expression levels in the central nervous system change during fetal development, infancy, childhood and adulthood suggesting that the protein's expression plays a crucial role in brain development. The CUL3 gene has been identified as a risk gene for neurodevelopmental disorders particularly Autism Spectrum Disorder.^[18]

Cancer

Deregulation of Cullin 3 expression level was observed in human cancers. It was shown that Cullin 3 is overexpressed in invasive cancers, and the protein expression level positively correlates with tumour stage. In breast cancer, the overexpression of Cullin 3 protein results in a decrease of Nrf2 protein level. This protein is a transcription factor regulating the expression of some detoxification and antioxidant enzymes. Another substrate of CRL complex is a candidate tumour suppressor protein RhoBTB2.^[19]

Interactions

CUL3 has been shown to interact with:

• CAND1,^[20]
• Cyclin E1,^[21]
• DCUN1D1,^[22]
• KEAP1,^{[23] [24]} and
• KLHL12.^[25]

Further reading

• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Michel JJ, Xiong Y . Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A . Cell Growth & Differentiation . 9 . 6 . 435–49 . June 1998 . 9663463 .
• Du M, Sansores-Garcia L, Zu Z, Wu KK . Cloning and expression analysis of a novel salicylate suppressible gene, Hs-CUL-3, a member of cullin/Cdc53 family . The Journal of Biological Chemistry . 273 . 38 . 24289–92 . September 1998 . 9733711 . 10.1074/jbc.273.38.24289 . free .
• Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 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 Research . 5 . 3 . 169–76 . June 1998 . 9734811 . 10.1093/dnares/5.3.169 . free .
• Ohta T, Michel JJ, Schottelius AJ, Xiong Y . ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity . Molecular Cell . 3 . 4 . 535–41 . April 1999 . 10230407 . 10.1016/S1097-2765(00)80482-7 . 19371828 . free .
• Singer JD, Gurian-West M, Clurman B, Roberts JM . Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells . Genes & Development . 13 . 18 . 2375–87 . September 1999 . 10500095 . 317026 . 10.1101/gad.13.18.2375 .
• Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K . Covalent modification of all members of human cullin family proteins by NEDD8 . Oncogene . 18 . 48 . 6829–34 . November 1999 . 10597293 . 10.1038/sj.onc.1203093 . free .
• Maeda I, Ohta T, Koizumi H, Fukuda M . In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3 . FEBS Letters . 494 . 3 . 181–5 . April 2001 . 11311237 . 10.1016/S0014-5793(01)02343-2 . 40693441 .
• Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ . Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome . Science . 292 . 5520 . 1382–5 . May 2001 . 11337588 . 10.1126/science.1059780 . 2001Sci...292.1382L . 14224920 .
• Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB . TIP120A associates with cullins and modulates ubiquitin ligase activity . The Journal of Biological Chemistry . 278 . 18 . 15905–10 . May 2003 . 12609982 . 10.1074/jbc.M213070200 . free .
• Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M . Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 . Molecular and Cellular Biology . 24 . 16 . 7130–9 . August 2004 . 15282312 . 479737 . 10.1128/MCB.24.16.7130-7139.2004 .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ . Immunoaffinity profiling of tyrosine phosphorylation in cancer cells . Nature Biotechnology . 23 . 1 . 94–101 . January 2005 . 15592455 . 10.1038/nbt1046 . 7200157 .
• Furukawa M, Xiong Y . BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase . Molecular and Cellular Biology . 25 . 1 . 162–71 . January 2005 . 15601839 . 538799 . 10.1128/MCB.25.1.162-171.2005 .
• Hernández-Muñoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M . Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase . Proceedings of the National Academy of Sciences of the United States of America . 102 . 21 . 7635–40 . May 2005 . 15897469 . 1140410 . 10.1073/pnas.0408918102 . free .
• Lu L, Zhou ZM, Huang XY, Xu M, Yin LL, Wang H, Xu ZY, Sha JH . Identification and characterization of cul-3b, a novel hominine CUL-3 transcript variant . Asian Journal of Andrology . 7 . 2 . 205–11 . June 2005 . 15897978 . 10.1111/j.1745-7262.2005.00024.x .

Notes and References

1. Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock EM . cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family . Cell . 85 . 6 . 829–39 . June 1996 . 8681378 . 10.1016/S0092-8674(00)81267-2 . 15805562 . free .
2. Wimuttisuk W, Singer JD . The Cullin3 ubiquitin ligase functions as a Nedd8-bound heterodimer . Molecular Biology of the Cell . 18 . 3 . 899–909 . March 2007 . 17192413 . 1805106 . 10.1091/mbc.E06-06-0542 .
3. Web site: Entrez Gene: CUL3 cullin 3.
4. Cheng J, Guo J, Wang Z, North BJ, Tao K, Dai X, Wei W . Functional analysis of Cullin 3 E3 ligases in tumorigenesis . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1869 . 1 . 11–28 . January 2018 . 29128526 . 10.1016/j.bbcan.2017.11.001 . 7076836 .
5. Sarikas A, Hartmann T, Pan Z . The cullin protein family . Genome Biol . 12 . 4 . 220 . 2011 . 21554755 . 3218854 . 10.1186/gb-2011-12-4-220 . free .
6. Dubiel D, Bintig W, Kähne T, Dubiel W, Naumann M . Cul3 neddylation is crucial for gradual lipid droplet formation during adipogenesis . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1864 . 8 . 1405–1412 . August 2017 . 28499918 . 10.1016/j.bbamcr.2017.05.009 .
7. Chen HY, Chen RH . Cullin 3 Ubiquitin Ligases in Cancer Biology: Functions and Therapeutic Implications . en . Frontiers in Oncology . 6 . 113 . 2016 . 27200299 . 4852199 . 10.3389/fonc.2016.00113 . free .
8. Petroski MD, Deshaies RJ . Function and regulation of cullin-RING ubiquitin ligases . En . Nature Reviews. Molecular Cell Biology . 6 . 1 . 9–20 . January 2005 . 15688063 . 10.1038/nrm1547 . 24159190 .
9. Cheng J, Guo J, Wang Z, North BJ, Tao K, Dai X, Wei W . Functional analysis of Cullin 3 E3 ligases in tumorigenesis . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1869 . 1 . 11–28 . January 2018 . 29128526 . 10.1016/j.bbcan.2017.11.001 . 7076836 .
10. Cheng J, Guo J, Wang Z, North BJ, Tao K, Dai X, Wei W . Functional analysis of Cullin 3 E3 ligases in tumorigenesis . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1869 . 1 . 11–28 . January 2018 . 29128526 . 10.1016/j.bbcan.2017.11.001 . 7076836 .
11. Bulatov E, Ciulli A . Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation . The Biochemical Journal . 467 . 3 . 365–86 . May 2015 . 25886174 . 4403949 . 10.1042/BJ20141450 .
12. Petroski MD, Deshaies RJ . Function and regulation of cullin-RING ubiquitin ligases . En . Nature Reviews. Molecular Cell Biology . 6 . 1 . 9–20 . January 2005 . 15688063 . 10.1038/nrm1547 . 24159190 .
13. Bulatov E, Ciulli A . Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation . The Biochemical Journal . 467 . 3 . 365–86 . May 2015 . 25886174 . 4403949 . 10.1042/BJ20141450 .
14. Chew EH, Hagen T . Substrate-mediated regulation of cullin neddylation . The Journal of Biological Chemistry . 282 . 23 . 17032–40 . June 2007 . 17439941 . 10.1074/jbc.M701153200 . free .
15. Soucy TA, Smith PG, Rolfe M . Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer . Clinical Cancer Research . 15 . 12 . 3912–6 . June 2009 . 19509147 . 10.1158/1078-0432.CCR-09-0343 . 17834925 .
16. Ferdaus MZ, McCormick JA . The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy . American Journal of Physiology. Renal Physiology . 310 . 11 . F1389–96 . June 2016 . 27076645 . 4935775 . 10.1152/ajprenal.00132.2016 .
17. Ferdaus MZ, McCormick JA . Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension . American Journal of Physiology. Renal Physiology . 314 . 5 . F915–F920 . May 2018 . 29361671 . 6031903 . 10.1152/ajprenal.00593.2017 .
18. Lin P, Yang J, Wu S, Ye T, Zhuang W, Wang W, Tan T . Current trends of high-risk gene Cul3 in neurodevelopmental disorders . Frontiers in Psychiatry . 14 . 1215110 . 2023 . 37575562 . 10416632 . 10.3389/fpsyt.2023.1215110 . free .
19. Haagenson KK, Tait L, Wang J, Shekhar MP, Polin L, Chen W, Wu GS . Cullin-3 protein expression levels correlate with breast cancer progression . Cancer Biology & Therapy . 13 . 11 . 1042–6 . September 2012 . 22825334 . 3461811 . 10.4161/cbt.21046 .
20. Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB . TIP120A associates with cullins and modulates ubiquitin ligase activity . The Journal of Biological Chemistry . 278 . 18 . 15905–10 . May 2003 . 12609982 . 10.1074/jbc.M213070200 . free .
21. Singer JD, Gurian-West M, Clurman B, Roberts JM . Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells . Genes & Development . 13 . 18 . 2375–87 . September 1999 . 10500095 . 317026 . 10.1101/gad.13.18.2375 .
22. Kim AY, Bommeljé CC, Lee BE, Yonekawa Y, Choi L, Morris LG, Huang G, Kaufman A, Ryan RJ, Hao B, Ramanathan Y, Singh B . SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation . The Journal of Biological Chemistry . 283 . 48 . 33211–20 . November 2008 . 18826954 . 2586271 . 10.1074/jbc.M804440200 . free .
23. Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD . Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction . Toxicology and Applied Pharmacology . 230 . 3 . 383–9 . August 2008 . 18417180 . 2610481 . 10.1016/j.taap.2008.03.003 .
24. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML . Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3 . Chemical Research in Toxicology . 21 . 3 . 705–10 . March 2008 . 18251510 . 10.1021/tx700302s . free .
25. Rondou P, Haegeman G, Vanhoenacker P, Van Craenenbroeck K . BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase . The Journal of Biological Chemistry . 283 . 17 . 11083–96 . April 2008 . 18303015 . 2431063 . 10.1074/jbc.M708473200 . free .