Key Points
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Ubiquitylation, or tagging proteins with ubiquitin, is a post-translational modification that targets proteins for degradation by the 26S proteasome or to other cellular fates, such as altered subcellular localization.
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The ubiquitylation reaction is carried out by E1, E2 and E3 enzymes. The E3 enzyme (a ubiquitin ligase) is responsible for substrate recognition. Most E3 enzymes belong either to the RING or the HECT superfamilies. Whereas RING E3 ubiquitin ligases act as scaffolds to bring the E2 enzyme near the substrates and facilitate the transfer of ubiquitin to the substrate, HECT E3 enzymes can directly transfer ubiquitin to the substrate.
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HECT-containing proteins are often regulated by intramolecular interactions or interactions with accessory proteins, and can recognize their substrates either directly or with the help of adaptor proteins.
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The HECT superfamily include members of the neuronal precursor cell expressed developmentally downregulated 4 (Nedd4) family, the HERC family and others, including E6-associated protein (E6AP), EDD and HUWE1.
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Recent advances in genetic studies of human diseases and in knockout animals have identified the crucial role of HECT proteins in the regulation of mammalian physiology and pathology.
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Loss or gain of function of HECT proteins result in animal diseases, including aberrant cellular and animal growth, cancer, neurological diseases, hypertension, immunological disorders such as autoimmunity, and aberrant response to viral infection.
Abstract
The ubiquitylation of proteins is carried out by E1, E2 and E3 (ubiquitin ligase) enzymes, and targets them for degradation or for other cellular fates. The HECT enzymes, including Nedd4 family members, are a major group of E3 enzymes that dictate the specificity of ubiquitylation. In addition to ubiquitylating proteins for degradation by the 26S proteasome, HECT E3 enzymes regulate the trafficking of many receptors, channels, transporters and viral proteins. The physiological functions of the yeast HECT E3 ligase Rsp5 are the best known, but the functions of HECT E3 enyzmes in metazoans are now becoming clearer from in vivo studies.
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References
Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).
Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin–binding proteins. Annu. Rev. Cell Dev. Biol. 19, 141–172 (2003).
Xu, P. et al. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 137, 133–145 (2009).
Li, W. et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS ONE 3, e1487 (2008).
Huibregtse, J. M., Scheffner, M., Beaudenon, S. & Howley, P. M. A family of proteins structurally and functionally related to the E6-AP ubiquitin–protein ligase. Proc. Natl Acad. Sci. USA 92, 2563–2567 (1995). The first identification of the HECT family of E3 ligases.
Kumar, S., Tomooka, Y. & Noda, M. Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem. Biophys. Res. Commun. 185, 1155–1161 (1992).
Plant, P. J. et al. Apical membrane targeting of Nedd4 is mediated by an association of its C2 domain with annexin XIIIb. J. Cell Biol. 149, 1473–1484 (2000).
Dunn, R., Klos, D. A., Adler, A. S. & Hicke, L. The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo. J. Cell Biol. 165, 135–144 (2004).
Morrione, A. et al. mGrb10 interacts with Nedd4. J. Biol. Chem. 274, 24094–24099 (1999).
Wiesner, S. et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell 130, 651–662 (2007).
Staub, O. et al. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J. 15, 2371–2380 (1996). Describes the discovery of the first substrate for a mammalian Nedd4 family member.
Kanelis, V., Rotin, D. & Forman-Kay, J. D. Solution structure of a Nedd4 WW domain–ENaC peptide complex. Nature Struct. Biol. 8, 407–412 (2001).
Garcia-Gonzalo, F. R. & Rosa, J. L. The HERC proteins: functional and evolutionary insights. Cell. Mol. Life Sci. 62, 1826–1838 (2005).
Renault, L., Kuhlmann, J., Henkel, A. & Wittinghofer, A. Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1). Cell 105, 245–255 (2001).
Huang, L. et al. Structure of an E6AP–UbcH7 complex: insights into ubiquitination by the E2–E3 enzyme cascade. Science 286, 1321–1326 (1999). Deciphers the first structure of a HECT domain.
Verdecia, M. A. et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol. Cell 11, 249–259 (2003).
Ogunjimi, A. A. et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol. Cell 19, 297–308 (2005).
Wang, M. & Pickart, C. M. Different HECT domain ubiquitin ligases employ distinct mechanisms of polyubiquitin chain synthesis. EMBO J. 24, 4324–4333 (2005).
Wang, M., Cheng, D., Peng, J. & Pickart, C. M. Molecular determinants of polyubiquitin linkage selection by an HECT ubiquitin ligase. EMBO J. 25, 1710–1719 (2006).
Fisk, H. A. & Yaffe, M. P. A role for ubiquitination in mitochondrial inheritance in Saccharomyces cerevisiae. J. Cell Biol. 145, 1199–1208 (1999).
Huibregtse, J. M., Yang, J. C. & Beaudenon, S. L. The large subunit of RNA polymerase II is a substrate of the Rsp5 ubiquitin–protein ligase. Proc. Natl Acad. Sci. USA 94, 3656–3661 (1997).
Somesh, B. P. et al. Communication between distant sites in RNA polymerase II through ubiquitylation factors and the polymerase CTD. Cell 129, 57–68 (2007).
Dupre, S., Urban-Grimal, D. & Haguenauer-Tsapis, R. Ubiquitin and endocytic internalization in yeast and animal cells. Biochim. Biophys. Acta 1695, 89–111 (2004).
Belgareh-Touze, N. et al. Versatile role of the yeast ubiquitin ligase Rsp5p in intracellular trafficking. Biochem. Soc. Trans. 36, 791–796 (2008).
Helliwell, S. B., Losko, S. & Kaiser, C. A. Components of a ubiquitin ligase complex specify polyubiquitination and intracellular trafficking of the general amino acid permease. J. Cell Biol. 153, 649–662 (2001).
Galan, J. M. & Haguenauer-Tsapis, R. Ubiquitin Lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO J. 16, 5847–5854 (1997).
Shih, S. C., Sloper-Mould, K. E. & Hicke, L. Monoubiquitin carries a novel internalization signal that is appended to activated receptors. EMBO J. 19, 187–198 (2000). Shows, for the first time, that monoubiquitylation serves as an endocytic signal.
Nefsky, B. & Beach, D. Pub1 acts as an E6-AP-like protein ubiquitin ligase in the degradation of cdc25. EMBO J. 15, 1301–1312 (1996).
Huang, K. et al. A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis. Gene 252, 137–145 (2000).
Astin, J. W., O'Neil, N. J. & Kuwabara, P. E. Nucleotide excision repair and the degradation of RNA pol II by the Caenorhabditis elegans XPA and Rsp5 orthologues, RAD-3 and WWP-1. DNA Repair (Amst.) 7, 267–280 (2008).
Shaye, D. D. & Greenwald, I. LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans. Development 132, 5081–5092 (2005).
Ing, B. et al. Regulation of Commissureless by the ubiquitin ligase DNedd4 is required for neuromuscular synaptogenesis in Drosophila melanogaster. Mol. Cell. Biol. 27, 481–496 (2007).
Sakata, T. et al. Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Curr. Biol. 14, 2228–2236 (2004).
Wilkin, M. B. et al. Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr. Biol. 14, 2237–2244 (2004).
Podos, S. D., Hanson, K. K., Wang, Y. C. & Ferguson, E. L. The DSmurf ubiquitin–protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis. Dev. Cell 1, 567–578 (2001).
Liang, Y. Y. et al. dSmurf selectively degrades decapentaplegic-activated MAD, and its overexpression disrupts imaginal disc development. J. Biol. Chem. 278, 26307–26310 (2003).
Cao, X. R. et al. Nedd4 controls animal growth by regulating IGF-1 signaling. Sci. Signal. 1, ra5 (2008). Identifies NEDD4 as a positive growth regulator of mammalian cells and tissues.
Fouladkou, F. et al. The ubiquitin ligase Nedd4–1 is dispensable for the regulation of PTEN stability and localization. Proc. Natl Acad. Sci. USA 105, 8585–8590 (2008).
Massague, J. & Gomis, R. R. The logic of TGFβ signaling. FEBS Lett. 580, 2811–2820 (2006).
Zhu, H., Kavsak, P., Abdollah, S., Wrana, J. L. & Thomsen, G. H. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687–693 (1999).
Yamashita, M. et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 121, 101–113 (2005).
Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005). Describes the important role of SMURF1 in the degradation of RhoA and the regulation of the epithelial-to-mesenchymal transition.
Zhang, Y., Chang, C., Gehling, D. J., Hemmati-Brivanlou, A. & Derynck, R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 98, 974–979 (2001).
Lin, X., Liang, M. & Feng, X. H. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-β signaling. J. Biol. Chem. 275, 36818–36822 (2000).
Kavsak, P. et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol. Cell 6, 1365–1375 (2000).
Bonni, S. et al. TGF-β induces assembly of a Smad2–Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nature Cell Biol. 3, 587–595 (2001).
Gao, M. et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271–275 (2004).
Chang, L. et al. The E3 ubiquitin ligase Itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. Cell 124, 601–613 (2006).
Rossi, M. et al. The ubiquitin–protein ligase Itch regulates p73 stability. EMBO J. 24, 836–848 (2005).
Rossi, M. et al. The E3 ubiquitin ligase Itch controls the protein stability of p63. Proc. Natl Acad. Sci. USA 103, 12753–12758 (2006).
Kamynina, E., Debonneville, C., Bens, M., Vandewalle, A. & Staub, O. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J. 15, 204–214 (2001).
Harvey, K. F., Dinudom, A., Cook, D. I. & Kumar, S. The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J. Biol. Chem. 276, 8597–8601 (2001).
Lu, C., Pribanic, S., Debonneville, A., Jiang, C. & Rotin, D. The PY motif of ENaC, mutated in Liddle syndrome, regulates channel internalization, sorting and mobilization from subapical pool. Traffic 8, 1246–1264 (2007).
Pak, Y., Glowacka, W. K., Bruce, M. C., Pham, N. & Rotin, D. Transport of LAPTM5 to lysosomes requires association with the ubiquitin ligase Nedd4, but not LAPTM5 ubiquitination. J. Cell Biol. 175, 631–645 (2006).
Saksena, S., Sun, J., Chu, T. & Emr, S. D. ESCRTing proteins in the endocytic pathway. Trends Biochem. Sci. 32, 561–573 (2007).
Morita, E. & Sundquist, W. I. Retrovirus budding. Annu. Rev. Cell Dev. Biol. 20, 395–425 (2004).
Okumura, A., Pitha, P. M. & Harty, R. N. ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc. Natl Acad. Sci. USA 105, 3974–3979 (2008).
Malakhova, O. A. & Zhang, D. E. ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. J. Biol. Chem. 283, 8783–8787 (2008). References 57 and 58 provide the first demonstration of inhibition of HECT ligase by a ubiquitin-like protein.
Wang, X. et al. NEDD4–1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128, 129–139 (2007).
Trotman, L. C. et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128, 141–156 (2007).
Yang, B. et al. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nature Immunol. 9, 1356–1363 (2008).
Perry, W. L. et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nature Genet. 18, 143–146 (1998).
Fang, D. et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nature Immunol. 3, 281–287 (2002). Reference 62 and 63 found that loss of the HECT E3 ligase ITCH causes immune defects.
Venuprasad, K. et al. Convergence of Itch-induced ubiquitination with MEKK1–JNK signaling in Th2 tolerance and airway inflammation. J. Clin. Invest. 116, 1117–1126 (2006).
Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunol. 5, 255–265 (2004).
Chen, C. et al. Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Oncogene 26, 2386–2394 (2007).
Chen, C., Zhou, Z., Ross, J. S., Zhou, W. & Dong, J. T. The amplified WWP1 gene is a potential molecular target in breast cancer. Int. J. Cancer 121, 80–87 (2007).
Chen, C. et al. Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells. J. Biol. Chem. 280, 41553–41561 (2005).
Laine, A. & Ronai, Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 26, 1477–1483 (2007).
Foot, N. J. et al. Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 112, 4268–4275 (2008). Provides an example of how specific mammalian adaptor proteins can mediate the regulation of a substrate by a HECT E3.
Lifton, R. P., Gharavi, A. G. & Geller, D. S. Molecular mechanisms of human hypertension. Cell 104, 545–556 (2001).
Shi, P. P. et al. Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4–2. Am. J. Physiol. Renal Physiol. 295, F462–F470 (2008).
Pradervand, S. et al. A mouse model for Liddle's syndrome. J. Am. Soc. Nephrol. 10, 2527–2533 (1999).
Miyazaki, K. et al. A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity. Biochem. Biophys. Res. Commun. 308, 106–113 (2003).
Li, Y. et al. A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-mediated apoptotic cell death in its catalytic activity-independent manner. Oncogene 27, 3700–3709 (2008).
Miyazaki, K. et al. NEDL1, a novel ubiquitin–protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1. J. Biol. Chem. 279, 11327–11335 (2004).
Garcia-Gonzalo, F. R., Bartrons, R., Ventura, F. & Rosa, J. L. Requirement of phosphatidylinositol-4,5-bisphosphate for HERC1-mediated guanine nucleotide release from ARF proteins. FEBS Lett. 579, 343–348 (2005).
Chong-Kopera, H. et al. TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J. Biol. Chem. 281, 8313–8316 (2006).
Lehman, A. L. et al. A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice. Proc. Natl Acad. Sci. USA 95, 9436–9441 (1998).
Sturm, R. A. et al. A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. Am. J. Hum. Genet. 82, 424–431 (2008).
Eiberg, H. et al. Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Hum. Genet. 123, 177–187 (2008). References 80 and 81 were the first to implicate HERC2 in the determination of eye colour.
Hochrainer, K., Kroismayr, R., Baranyi, U., Binder, B. R. & Lipp, J. Highly homologous HERC proteins localize to endosomes and exhibit specific interactions with hPLIC and Nm23B. Cell. Mol. Life Sci. 65, 2105–2117 (2008).
Cruz, C., Ventura, F., Bartrons, R. & Rosa, J. L. HERC3 binding to and regulation by ubiquitin. FEBS Lett. 488, 74–80 (2001).
Rodriguez, C. I. & Stewart, C. L. Disruption of the ubiquitin ligase HERC4 causes defects in spermatozoon maturation and impaired fertility. Dev. Biol. 312, 501–508 (2007).
Kroismayr, R. et al. HERC5, a HECT E3 ubiquitin ligase tightly regulated in LPS activated endothelial cells. J. Cell Sci. 117, 4749–4756 (2004).
Dastur, A., Beaudenon, S., Kelley, M., Krug, R. M. & Huibregtse, J. M. Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells. J. Biol. Chem. 281, 4334–4338 (2006).
Wong, J. J., Pung, Y. F., Sze, N. S. & Chin, K. C. HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets. Proc. Natl Acad. Sci. USA 103, 10735–10740 (2006).
Yoshida, M. et al. Poly(A) binding protein (PABP) homeostasis is mediated by the stability of its inhibitor, Paip2. EMBO J. 25, 1934–1944 (2006).
Henderson, M. J. et al. EDD mediates DNA damage-induced activation of CHK2. J. Biol. Chem. 281, 39990–40000 (2006).
Ohshima, R. et al. Putative tumor suppressor EDD interacts with and up-regulates APC. Genes Cells 12, 1339–1345 (2007).
Saunders, D. N. et al. Edd, the murine hyperplastic disc gene, is essential for yolk sac vascularization and chorioallantoic fusion. Mol. Cell. Biol. 24, 7225–7234 (2004).
Chen, D. et al. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121, 1071–1083 (2005).
Zhong, Q., Gao, W., Du, F. & Wang, X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095 (2005).
Adhikary, S. et al. The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell 123, 409–421 (2005).
Zhao, X. et al. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nature Cell Biol. 10, 643–653 (2008). This important work identified NMYC as the substrate for HUWE1 and thus the control of HUWE1 in neuronal differentiation.
Herold, S. et al. Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1. EMBO J. 27, 2851–2861 (2008).
Scheffner, M. & Staub, O. HECT E3s and human disease. BMC Biochem. 8, S6 (2007).
Froyen, G. et al. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am. J. Hum. Genet. 82, 432–443 (2008).
Vu, T. H. & Hoffman, A. R. Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nature Genet. 17, 12–13 (1997).
Rougeulle, C., Glatt, H. & Lalande, M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nature Genet. 17, 14–15 (1997). References 99 and 100 identified E6AP as an imprinted gene and found that mutations in the E6AP gene cause Angelman syndrome, a neurodevelopmental disorder.
Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15, 70–73 (1997).
Jiang, Y. H. et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998).
Colas, D., Wagstaff, J., Fort, P., Salvert, D. & Sarda, N. Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome. Neurobiol. Dis. 20, 471–478 (2005).
Wu, Y. et al. A Drosophila model for Angelman syndrome. Proc. Natl Acad. Sci. USA 105, 12399–12404 (2008).
Scheffner, M., Huibregtse, J. M., Vierstra, R. D. & Howley, P. M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin–protein ligase in the ubiquitination of p53. Cell 75, 495–505 (1993). This seminal work identified E6AP as the E3 ligase for the tumour suppressor p53 in HPV-infected cells. Such an infection can lead to cervical cancer.
Martin, P., Martin, A. & Shearn, A. Studies of l(3)c43hs1 a polyphasic, temperature-sensitive mutant of Drosophila melanogaster with a variety of imaginal disc defects. Dev. Biol. 55, 213–232 (1977).
Lee, J. D., Amanai, K., Shearn, A. & Treisman, J. E. The ubiquitin ligase Hyperplastic discs negatively regulates hedgehog and decapentaplegic expression by independent mechanisms. Development 129, 5697–5706 (2002).
Clancy, J. L. et al. EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer. Oncogene 22, 5070–5081 (2003).
Fuja, T. J., Lin, F., Osann, K. E. & Bryant, P. J. Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 ε, DLG1, and EDD/hHYD in mammary ductal carcinoma. Cancer Res. 64, 942–951 (2004).
Anglesio, M. S. et al. Differential expression of a novel ankyrin containing E3 ubiquitin–protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney. Hum. Mol. Genet. 13, 2061–2074 (2004).
Hibi, K. et al. Aberrant methylation of the HACE1 gene is frequently detected in advanced colorectal cancer. Anticancer Res. 28, 1581–1584 (2008).
Zhang, L. et al. The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nature Med. 13, 1060–1069 (2007). Provides direct in vivo evidence using knockout mice for the function of HACE1 as a tumour suppressor.
Zohn, I. E., Anderson, K. V. & Niswander, L. The Hectd1 ubiquitin ligase is required for development of the head mesenchyme and neural tube closure. Dev. Biol. 306, 208–221 (2007).
Crosas, B. et al. Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127, 1401–1413 (2006).
Brooks, W. S. et al. G2E3 is a dual function ubiquitin ligase required for early embryonic development. J. Biol. Chem. 283, 22304–22315 (2008).
Debonneville, C. et al. Phosphorylation of Nedd4–2 by Sgk1 regulates epithelial Na+ channel cell surface expression. EMBO J. 20, 7052–7059 (2001).
Snyder, P. M., Olson, D. R. & Thomas, B. C. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. J. Biol. Chem. 277, 5–8 (2002).
Oberst, A. et al. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch. Proc. Natl Acad. Sci. USA 104, 11280–11285 (2007).
Gallagher, E., Gao, M., Liu, Y. C. & Karin, M. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. Proc. Natl Acad. Sci. USA 103, 1717–1722 (2006).
Bruce, M. C. et al. Regulation of Nedd4–2 self-ubiquitination and stability by a PY motif located within its HECT-domain. Biochem. J. 415, 155–163 (2008).
Lu, K. et al. Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1. Nature Cell Biol. 10, 994–1002 (2008).
Spana, E. P. & Doe, C. Q. Numb antagonizes Notch signaling to specify sibling neuron cell fates. Neuron 17, 21–26 (1996).
McGill, M. A. & McGlade, C. J. Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J. Biol. Chem. 278, 23196–23203 (2003).
Kee, Y., Lyon, N. & Huibregtse, J. M. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme. EMBO J. 24, 2414–2424 (2005).
Liu, X. F. & Culotta, V. C. Post-translation control of Nramp metal transport in yeast. Role of metal ions and the BSD2 gene. J. Biol. Chem. 274, 4863–4868 (1999).
Hettema, E. H., Valdez-Taubas, J. & Pelham, H. R. Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins. EMBO J. 23, 1279–1288 (2004).
Liu, X. F., Supek, F., Nelson, N. & Culotta, V. C. Negative control of heavy metal uptake by the Saccharomyces cerevisiae BSD2 gene. J. Biol. Chem. 272, 11763–11769 (1997).
Stimpson, H. E., Lewis, M. J. & Pelham, H. R. Transferrin receptor-like proteins control the degradation of a yeast metal transporter. EMBO J. 25, 662–672 (2006).
Shearwin-Whyatt, L., Dalton, H. E., Foot, N. & Kumar, S. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins. Bioessays 28, 617–628 (2006).
Oliver, P. M. et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity 25, 929–940 (2006).
Putz, U. et al. Nedd4-family interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4-family proteins. J. Biol. Chem. 283, 32621–32627 (2008).
Nikko, E., Sullivan, J. A. & Pelham, H. R. Arrestin-like proteins mediate ubiquitination and endocytosis of the yeast metal transporter Smf1. EMBO Rep. 9, 1216–1221 (2008).
Lin, C. H., Macgurn, J. A., Chu, T., Stefan, C. J. & Emr, S. D. Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and protein turnover at the cell surface. Cell 135, 714–725 (2008). References 132 and 133 provide evidence that arrestin-like proteins act as adaptors for Rsp5 to regulate protein turnover and endocytosis.
Leon, S., Erpapazoglou, Z. & Haguenauer-Tsapis, R. Ear1p and Ssh4p are new adaptors of the ubiquitin ligase Rsp5p for cargo ubiquitylation and sorting at multivesicular bodies. Mol. Biol. Cell 19, 2379–2388 (2008).
Gupta, R. et al. Ubiquitination screen using protein microarrays for comprehensive identification of Rsp5 substrates in yeast. Mol. Syst. Biol. 3, 116 (2007).
Yen, H. C., Xu, Q., Chou, D. M., Zhao, Z. & Elledge, S. J. Global protein stability profiling in mammalian cells. Science 322, 918–923 (2008). Describes a novel proteomic approach to identify substrates for E3 ligases in vivo .
Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nature Cell Biol. 11, 123–132 (2009).
Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136, 1098–1109 (2009).
Acknowledgements
Research on ubiquitin pathways in the Rotin laboratory is supported by the Canadian Institute of Health Research and the National Cancer Institute of Canada/Canadian Cancer Society, and research in the Kumar laboratory by the National Health and Medical Research Council of Australia and the Australian Research Council. The authors thank the members of their respective laboratories for helpful comments and apologize to those whose work could not be cited owing to space limitations.
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DATABASES
OMIM
FURTHER INFORMATION
Glossary
- 26S proteasome
-
A multiprotein complex that comprises 19S regulatory and 20S catalytic subcomplexes and that recognizes and breaks down ubiquitylated proteins.
- WW domain
-
A protein–protein interaction domain that contains two conserved Trp residues.
- Multivesicular body
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(MVB). An intermediate organelle that is involved in protein sorting in the lysosomal degradation pathway.
- PY motif
-
A short protein motif, either Pro-Pro-X-Tyr or Leu-Pro-X-Tyr (where X indicates any amino acid), that binds WW domains.
- GEF
-
(Guanine nucleotide-exchange factor). A factor that stimulates the activity of GTPases by catalysing the exchange of GDP for GTP.
- Lysosome
-
A eukaryotic organelle that carries proteolytic enzymes, which degrade proteins targeted to the compartment. In yeast, the lysosome is often called the vacuole.
- Tight junction
-
A cell–cell junction that tightly adheres adjacent epithelial cells and prevents the paracellular passage of solutes and ions.
- Gag
-
The gag gene encodes the viral matrix, capsid and nucleoproteins. These proteins are synthesized as a polyprotein precursor, which is cleaved by proteases into products that associate with the nucleoprotein core of the virion.
- VP40
-
(Viral protein 40). The major matrix protein of Ebola virus that is essential for viral assembly and budding.
- M protein
-
Rhabdovirus matrix (M) protein is required to condense and target the viral ribonucleoprotein coil to the plasma membrane.
- Z region
-
A region of arenavirus that encodes a small protein (Z) that contains a Pro-rich region and a RING domain.
- T helper 2
-
A subset of T helper lymphocytes that inhibits the cell-mediated immune response.
- GRF
-
(Guanine nucleotide-releasing factor). A protein that catalyses the release of GDP.
- ISGylation
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A similar process to ubiquitylation in which interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, is covalently attached to a specific substrate.
- UBR1-like zinc finger
-
A domain in yeast Ubr1 that is involved in the recognition of substrates of the N-end rule, the ubiquitin-dependent pathway by which target proteins are degraded through their destabilizing amino-terminal residues. Zinc finger domains are small motifs that bind one or more zinc atoms.
- Imprinted region
-
A region in the chromosome that is transcribed only from the maternal or paternal chromosome.
- Telomerase
-
An enzyme that elongates the 3′ ends (telomeres) of DNA.
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Rotin, D., Kumar, S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10, 398–409 (2009). https://doi.org/10.1038/nrm2690
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DOI: https://doi.org/10.1038/nrm2690
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