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Cullin-3

Definition:

Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, MACROH2A1 and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL; these complexes have lower ubiquitin ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; by mediating ubiquitination of WNK4. The BCR(KLHL20) E3 ubiquitin ligase complex is involved in interferon response and anterograde Golgi to endosome transport: it mediates both ubiquitination leading to degradation and 'Lys-33'-linked ubiquitination. The BCR(KLHL21) E3 ubiquitin ligase complex regulates localization of the chromosomal passenger complex (CPC) from chromosomes to the spindle midzone in anaphase and mediates the ubiquitination of AURKB. The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation. The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway. The BCR(KLHL25) ubiquitin ligase complex is involved in translational homeostasis by mediating ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1). The BCR(KLHL25) ubiquitin ligase complex is also involved in lipid synthesis by mediating ubiquitination and degradation of ACLY. The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1, leading to remodel the translational program of differentiating cells in favor of neural crest specification. Involved in ubiquitination of cyclin E and of cyclin D1 (in vitro) thus involved in regulation of G1/S transition. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and RBX1, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. The BCR(KCTD17) E3 ubiquitin ligase complex mediates ubiquitination and degradation of TCHP, a down-regulator of cilium assembly, thereby inducing ciliogenesis. The BCR(KLHL24) E3 ubiquitin ligase complex mediates ubiquitination of KRT14, controls KRT14 levels during keratinocytes differentiation, and is essential for skin integrity. The BCR(KLHL18) E3 ubiquitin ligase complex mediates the ubiquitination of AURKA leading to its activation at the centrosome which is required for initiating mitotic entry. The BCR(KEAP1) E3 ubiquitin ligase complex acts as a key sensor of oxidative and electrophilic stress by mediating ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions mediates 'Lys-48' ubiquitination and proteasomal degradation of TIAM1. By controlling the ubiquitination of that RAC1 guanine exchange factors (GEF), regulates RAC1 signal transduction and downstream biological processes including the organization of the cytoskeleton, cell migration and cell proliferation.

References:

[1]. Jochen Beck, et al. Ubiquitylation-dependent localization of PLK1 in mitosis. Nat Cell Biol. 2013 Apr;15(4):430-9. [Content Brief]

[2]. I Maeda, et al. In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3. FEBS Lett. 2001 Apr 13;494(3):181-5. [Content Brief]

[3]. Anindita Bhoumik, et al. Regulation of TIP60 by ATF2 modulates ATM activation. J Biol Chem. 2008 Jun 20;283(25):17605-14. [Content Brief]

[4]. Lingyan Jin, et al. Ubiquitin-dependent regulation of COPII coat size and function. Nature. 2012 Feb 22;482(7386):495-500. [Content Brief]

[5]. Akiko Yanagiya, et al. Translational homeostasis via the mRNA cap-binding protein, eIF4E. Mol Cell. 2012 Jun 29;46(6):847-58. [Content Brief]

[6]. Saili Moghe, et al. The CUL3-KLHL18 ligase regulates mitotic entry and ubiquitylates Aurora-A. Biol Open. 2012 Feb 15;1(2):82-91. [Content Brief]

[7]. Achim Werner, et al. Cell-fate determination by ubiquitin-dependent regulation of translation. Nature. 2015 Sep 24;525(7570):523-7. [Content Brief]

[8]. Mai Wakabayashi, et al. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep. 2013 Mar 28;3(3):858-68. [Content Brief]

[9]. Colleen A McGourty, et al. Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor. Cell. 2016 Oct 6;167(2):525-538.e14. [Content Brief]

[10]. J D Singer, et al. Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev. 1999 Sep 15;13(18):2375-87. [Content Brief]

[11]. Jie Chen, et al. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature. 2018 May;557(7706):585-589. [Content Brief]

[12]. Kousuke Kasahara, et al. Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension. Nat Commun. 2014 Oct 1;5:5081. [Content Brief]

[13]. Wesley J Errington, et al. Adaptor protein self-assembly drives the control of a cullin-RING ubiquitin ligase. Structure. 2012 Jul 3;20(7):1141-53. [Content Brief]

[14]. Daniel C Scott, et al. Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation. Cell. 2016 Aug 25;166(5):1198-1214.e24. [Content Brief]

[15]. Mei-Yao Lin, et al. PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth. J Cell Biol. 2011 Jun 13;193(6):985-94. [Content Brief]

[16]. Yu-Ru Lee, et al. The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. EMBO J. 2010 May 19;29(10):1748-61. [Content Brief]

[17]. Zhimiao Lin, et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet. 2016 Dec;48(12):1508-1516. [Content Brief]

[18]. Cen Zhang, et al. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 2016 Sep 1;30(17):1956-70. [Content Brief]

[19]. Wei-Chien Yuan, et al. K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ubiquitin E3 Ligase Regulates Protein Trafficking. Mol Cell. 2014 May 22;54(4):586-600. [Content Brief]

[20]. Cristina M Cummings, et al. The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is required for normal mitosis in mammalian cells. J Biol Chem. 2009 Apr 24;284(17):11663-75. [Content Brief]

[21]. Manabu Furukawa, et al. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol. 2005 Jan;25(1):162-71. [Content Brief]

[22]. Heide Marika Genau, et al. CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling. Mol Cell. 2015 Mar 19;57(6):995-1010. [Content Brief]

[23]. Bogyou Kim, et al. Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex. Biochem Biophys Res Commun. 2011 Dec 2;415(4):720-6. [Content Brief]

[24]. Shigeru Shibata, et al. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7838-43. [Content Brief]

[25]. Sarah Maerki, et al. The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midzone microtubules in anaphase and is required for cytokinesis. J Cell Biol. 2009 Dec 14;187(6):791-800. [Content Brief]

[26]. Wei-Chien Yuan, et al. A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell. 2011 Aug 16;20(2):214-28. [Content Brief]

[27]. Jeong Eun Kwon, et al. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. [Content Brief]

[28]. Izabela Sumara, et al. A Cul3-based E3 ligase removes Aurora B from mitotic chromosomes, regulating mitotic progression and completion of cytokinesis in human cells. Dev Cell. 2007 Jun;12(6):887-900. [Content Brief]

[29]. Donna D Zhang, et al. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem. 2005 Aug 26;280(34):30091-9. [Content Brief]

[30]. Aimee L Eggler, et al. Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10070-5. [Content Brief]

[31]. Inmaculada Hernández-Muñoz, et al. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. [Content Brief]

[32]. Akihito Ohta, et al. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J. 2013 Apr 1;451(1):111-22. [Content Brief]

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