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Functional and pathological relevance of HERC family proteins: a decade later

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Abstract

The HERC gene family encodes proteins with two characteristic domains in their sequence: the HECT domain and the RCC1-like domain (RLD). In humans, the HERC family comprises six members that can be divided into two groups based on their molecular mass and domain structure. Whereas large HERCs (HERC1 and HERC2) contain one HECT and more than one RLD, small HERCs (HERC3-6) possess single HECT and RLD domains. Accumulating evidence shows the HERC family proteins to be key components of a wide range of cellular functions, including neurodevelopment, DNA damage repair, cell growth and immune response. Considering the significant recent advances made regarding HERC functionality, an updated review summarizing the progress is greatly needed at 10 years since the last HERC review. We provide an integrated view of HERC function and go into detail about its implications for several human diseases such as cancer and neurological disorders.

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References

  1. Garcia-Gonzalo FR, Rosa JL (2005) The HERC proteins: functional and evolutionary insights. Cell Mol Life Sci 62:1826–1838. doi:10.1007/s00018-005-5119-y

    Article  CAS  PubMed  Google Scholar 

  2. Huibregtse JM, Scheffner M, Beaudenon S, Howley PM (1995) A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase [published erratum appears in Proc Natl Acad Sci USA 1995 May 23;92(11):5249]. Proc Natl Acad Sci USA 92:2563–2567

  3. Vittal V, Stewart MD, Brzovic PS, Klevit RE (2015) Regulating the regulators: recent revelations in the control of E3 ubiquitin ligases. J Biol Chem 290:21244–21251. doi:10.1074/jbc.R115.675165

    Article  CAS  PubMed  Google Scholar 

  4. Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10:398–409. doi:10.1038/nrm2690

    Article  CAS  PubMed  Google Scholar 

  5. Metzger MB, Hristova VA, Weissman AM (2012) HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci 125:531–537. doi:10.1242/jcs.091777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Enserink JM (2015) Sumo and the cellular stress response. Cell Div 10:4. doi:10.1186/s13008-015-0010-1

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cajee U-F, Hull R, Ntwasa M (2012) Modification by ubiquitin-like proteins: significance in apoptosis and autophagy pathways. Int J Mol Sci 13:11804–11831. doi:10.3390/ijms130911804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lippai M, Lőw P (2014) The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. Biomed Res Int 2014:832704. doi:10.1155/2014/832704

    Article  PubMed  PubMed Central  Google Scholar 

  9. Morales DJ, Lenschow DJ (2013) The antiviral activities of ISG15. J Mol Biol 425:4995–5008. doi:10.1016/j.jmb.2013.09.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ohtsubo M, Kai R, Furuno N et al (1987) Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes Dev 1:585–593. doi:10.1101/gad.1.6.585

    Article  CAS  PubMed  Google Scholar 

  11. Renault L, Nassar N, Vetter I et al (1998) The 1.7 A crystal structure of the regulator of chromosome condensation (RCC1) reveals a seven-bladed propeller. Nature 392:97–101. doi:10.1038/32204

    Article  CAS  PubMed  Google Scholar 

  12. Renault L, Kuhlmann J, Henkel A, Wittinghofer A (2001) Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1). Cell 105:245–255. doi:10.1016/S0092-8674(01)00315-4

    Article  CAS  PubMed  Google Scholar 

  13. Nemergut ME, Mizzen CA, Stukenberg T et al (2001) Chromatin docking and exchange activity enhancement of RCC1 by histones H2A and H2B. Science 292:1540–1543. doi:10.1126/science.292.5521.1540

    Article  CAS  PubMed  Google Scholar 

  14. Hadjebi O, Casas-Terradellas E, Garcia-Gonzalo FR, Rosa JL (2008) The RCC1 superfamily: from genes, to function, to disease. Biochim Biophys Acta Mol Cell Res 1783:1467–1479. doi:10.1016/j.bbamcr.2008.03.015

    Article  CAS  Google Scholar 

  15. Rosa JL, Casaroli-Marano RP, Buckler AJ et al (1996) p619, a giant protein related to the chromosome condensation regulator RCC1, stimulates guanine nucleotide exchange on ARF1 and Rab proteins. EMBO J 15:4262–4273

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cruz C, Paladugu A, Ventura F, et al. (1999) Assignment of the human P532 gene (HERC1) to chromosome 15q22 by fluorescence in situ hybridization. Cytogenet Cell Genet 86:68–69. doi:15414

  17. Garcia-Gonzalo FR, Bartrons R, Ventura F, Rosa JL (2005) Requirement of phosphatidylinositol-4,5-bisphosphate for HERC1-mediated guanine nucleotide release from ARF proteins. FEBS Lett 579:343–348. doi:10.1016/j.febslet.2004.11.095

    Article  CAS  PubMed  Google Scholar 

  18. Rosa JL, Barbacid M (1997) A giant protein that stimulates guanine nucleotide exchange on ARF1 and Rab proteins forms a cytosolic ternary complex with clathrin and Hsp70. Oncogene 15:1–6. doi:10.1038/sj.onc.1201170

    Article  CAS  PubMed  Google Scholar 

  19. Garcia-Gonzalo FR, Muñoz P, González E et al (2004) The giant protein HERC1 is recruited to aluminum fluoride-induced actin-rich surface protrusions in HeLa cells. FEBS Lett 559:77–83. doi:10.1016/S0014-5793(04)00030-4

    Article  CAS  PubMed  Google Scholar 

  20. Schwarz SE, Rosa JL, Scheffner M (1998) Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7. J Biol Chem 273:12148–12154. doi:10.1074/jbc.273.20.12148

    Article  CAS  PubMed  Google Scholar 

  21. Garcia-Gonzalo FR, Cruz C, Muñoz P et al (2003) Interaction between HERC1 and M2-type pyruvate kinase. FEBS Lett 539:78–84

    Article  CAS  PubMed  Google Scholar 

  22. Chong-Kopera H, Inoki K, Li Y et al (2006) TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J Biol Chem 281:8313–8316. doi:10.1074/jbc.C500451200

    Article  CAS  PubMed  Google Scholar 

  23. Orlova KA, Crino PB (2010) The tuberous sclerosis complex. Ann N Y Acad Sci 1184:87–105. doi:10.1111/j.1749-6632.2009.05117.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Diouf B, Cheng Q, Krynetskaia NF et al (2011) Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nat Med 17:1298–1303. doi:10.1038/nm.2430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Holloway A, Simmonds M, Azad A et al (2015) Resistance to UV-induced apoptosis by β-HPV5 E6 involves targeting of activated BAK for proteolysis by recruitment of the HERC1 ubiquitin ligase. Int J Cancer 136:2831–2843. doi:10.1002/ijc.29350

    Article  CAS  PubMed  Google Scholar 

  26. Neumann M, Vosberg S, Schlee C et al (2015) Mutational spectrum of adult T-ALL. Oncotarget 6:2754–2766

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mashimo T, Hadjebi O, Amair-Pinedo F et al (2009) Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase. PLoS Genet. doi:10.1371/journal.pgen.1000784

    PubMed  PubMed Central  Google Scholar 

  28. Bachiller S, Rybkina T, Porras-García E et al (2015) The HERC1 E3 ubiquitin ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction. Cell Mol Life Sci 72:2961–2971. doi:10.1007/s00018-015-1878-2

    Article  CAS  PubMed  Google Scholar 

  29. Ortega-Recalde O, Beltrán OI, Gálvez JM et al (2015) Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability. Clin Genet. doi:10.1111/cge.12634

    PubMed  Google Scholar 

  30. Nguyen LS, Schneider T, Rio M et al (2015) A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy. Eur J Hum Genet. doi:10.1038/ejhg.2015.140

    Google Scholar 

  31. Lehman AL, Nakatsu Y, Ching A et al (1998) A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice. Proc Natl Acad Sci USA 95:9436–9441. doi:10.1073/pnas.95.16.9436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Walkowicz M, Yonggang J, Xiaojia R et al (1999) Molecular characterization of radiation- and chemically induced mutations associated with neuromuscular tremors, runting, juvenile lethality, and sperm defects in jdf2 mice. Mamm Genome 10:870–878. doi:10.1007/s003359901106

    Article  CAS  PubMed  Google Scholar 

  33. Ji Y, Walkowicz MJ, Buiting K et al (1999) The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities. Hum Mol Genet 8:533–542

    Article  CAS  PubMed  Google Scholar 

  34. Nicholls RD, Knepper JL (2001) Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genom Hum Genet 2:153–175. doi:10.1146/annurev.genom.2.1.153

    Article  CAS  Google Scholar 

  35. Puffenberger EG, Jinks RN, Wang H et al (2012) A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat 33:1639–1646. doi:10.1002/humu.22237

    Article  CAS  PubMed  Google Scholar 

  36. Harlalka GV, Baple EL, Cross H et al (2013) Mutation of HERC2 causes developmental delay with Angelman-like features. J Med Genet 50:65–73. doi:10.1136/jmedgenet-2012-101367

    Article  CAS  PubMed  Google Scholar 

  37. Kühnle S, Kogel U, Glockzin S et al (2011) Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2. J Biol Chem 286:19410–19416. doi:10.1074/jbc.M110.205211

    Article  PubMed  PubMed Central  Google Scholar 

  38. Imai Y, Kobayashi Y, Inoshita T et al (2015) The Parkinson’s disease-associated protein kinase LRRK2 modulates notch signaling through the endosomal pathway. PLoS Genet 11:e1005503. doi:10.1371/journal.pgen.1005503

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wu W, Sato K, Koike A et al (2010) HERC2 is an E3 ligase that targets BRCA1 for degradation. Cancer Res 70:6384–6392. doi:10.1158/0008-5472.CAN-10-1304

    Article  CAS  PubMed  Google Scholar 

  40. Kang T-H, Lindsey-Boltz LA, Reardon JT, Sancar A (2010) Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci USA 107:4890–4895. doi:10.1073/pnas.0915085107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grossberger R, Gieffers C, Zachariae W et al (1999) Characterization of the DOC1/APC10 subunit of the yeast and the human anaphase-promoting complex. J Biol Chem 274:14500–14507

    Article  CAS  PubMed  Google Scholar 

  42. Passmore LA, McCormack EA, Au SWN et al (2003) Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition. EMBO J 22:786–796. doi:10.1093/emboj/cdg084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Itoh M, Kim C-H, Palardy G et al (2003) Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell 4:67–82

    Article  CAS  PubMed  Google Scholar 

  44. Kasper JS, Arai T, DeCaprio JA (2006) A novel p53-binding domain in CUL7. Biochem Biophys Res Commun 348:132–138. doi:10.1016/j.bbrc.2006.07.013

    Article  CAS  PubMed  Google Scholar 

  45. Cubillos-Rojas M, Amair-Pinedo F, Peiró-Jordán R et al (2014) The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization. J Biol Chem 289:14782–14795. doi:10.1074/jbc.M113.527978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Danielsen JR, Povlsen LK, Villumsen BH et al (2012) DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger. J Cell Biol 197:179–187. doi:10.1083/jcb.201106152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kang TH, Reardon JT, Sancar A (2011) Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein. Nucleic Acids Res 39:3176–3187. doi:10.1093/nar/gkq1318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee T-H, Park J-M, Leem S-H, Kang T-H (2014) Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair. Oncogene 33:19–25. doi:10.1038/onc.2012.539

    Article  CAS  PubMed  Google Scholar 

  49. Peng Y, Dai H, Wang E et al (2015) TUSC4 functions as a tumor suppressor by regulating BRCA1 stability. Cancer Res 75:378–386. doi:10.1158/0008-5472.CAN-14-2315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Izawa N, Wu W, Sato K et al (2011) HERC2 interacts with claspin and regulates DNA origin firing and replication fork progression. Cancer Res 71:5621–5625. doi:10.1158/0008-5472.CAN-11-0385

    Article  CAS  PubMed  Google Scholar 

  51. Yuan J, Luo K, Deng M et al (2014) HERC2-USP20 axis regulates DNA damage checkpoint through Claspin. Nucleic Acids Res 42:13110–13121. doi:10.1093/nar/gku1034

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhu M, Zhao H, Liao J, Xu X (2014) HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability. Nucleic Acids Res 42:13074–13081. doi:10.1093/nar/gku978

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bekker-Jensen S, Rendtlew Danielsen J, Fugger K et al (2010) HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat Cell Biol 12:80–86. doi:10.1038/ncb2008 (sup pp 1–12)

  54. Oestergaard VH, Pentzold C, Pedersen RT et al (2012) RNF8 and RNF168 but not HERC2 are required for DNA damage-induced ubiquitylation in chicken DT40 cells. DNA Repair (Amst) 11:892–905. doi:10.1016/j.dnarep.2012.08.005

    Article  CAS  Google Scholar 

  55. Zhang Z, Yang H, Wang H (2014) The histone H2A deubiquitinase USP16 interacts with HERC2 and fine-tunes cellular response to DNA damage. J Biol Chem 289:32883–32894. doi:10.1074/jbc.M114.599605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yoo NJ, Park SW, Lee SH (2011) Frameshift mutations of ubiquitination-related genes HERC2, HERC3, TRIP12, UBE2Q1 and UBE4B in gastric and colorectal carcinomas with microsatellite instability. Pathology 43:753–755. doi:10.1097/PAT.0b013e32834c7e78

    Article  CAS  PubMed  Google Scholar 

  57. Martinez-Noel G, Galligan JT, Sowa ME et al (2012) Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol 32:3095–3106. doi:10.1128/MCB.00201-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ibarrola-Villava M, Fernandez LP, Pita G et al (2010) Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2. Exp Dermatol 19:836–844. doi:10.1111/j.1600-0625.2010.01115.x

    Article  CAS  PubMed  Google Scholar 

  59. Al-Hakim AK, Bashkurov M, Gingras A-C et al (2012) Interaction proteomics identify NEURL4 and the HECT E3 ligase HERC2 as novel modulators of centrosome architecture. Mol Cell Proteom 11:M111.014233–M111.014233. doi:10.1074/mcp.M111.014233

  60. Chan NC, Den Besten W, Sweredoski MJ et al (2014) Degradation of the deubiquitinating enzyme USP33 is mediated by p97 and the ubiquitin ligase HERC2. J Biol Chem 289:19789–19798. doi:10.1074/jbc.M114.569392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Moroishi T, Yamauchi T, Nishiyama M, Nakayama KI (2014) HERC2 targets the iron regulator FBXL5 for degradation and modulates iron metabolism. J Biol Chem 289:16430–16441. doi:10.1074/jbc.M113.541490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mancias JD, Pontano Vaites L, Nissim S et al (1030) Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. doi:10.7554/eLife.8

    Google Scholar 

  63. Galligan JT, Martinez-Noël G, Arndt V et al (2015) Proteomic analysis and identification of cellular interactors of the giant ubiquitin ligase HERC2. J Proteome Res 14:953–966. doi:10.1021/pr501005v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. White D, Rabago-Smith M (2011) Genotype-phenotype associations and human eye color. J Hum Genet 56:5–7. doi:10.1038/jhg.2010.126

    Article  CAS  PubMed  Google Scholar 

  65. Donnelly MP, Paschou P, Grigorenko E et al (2012) A global view of the OCA2-HERC2 region and pigmentation. Hum Genet 131:683–696. doi:10.1007/s00439-011-1110-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nomura N, Miyajima N, Sazuka T et al (1994) Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1. DNA Res 1:27–35

    Article  CAS  PubMed  Google Scholar 

  67. Cruz C, Nadal M, Ventura F, et al. (1999) The human HERC3 gene maps to chromosome 4q21 by fluorescence in situ hybridization. Cytogenet Cell Genet 87:263–264. doi:15442

  68. Hochrainer K, Mayer H, Baranyi U et al (2005) The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects. Genomics 85:153–164. doi:10.1016/j.ygeno.2004.10.006

    Article  CAS  PubMed  Google Scholar 

  69. Davies W, Smith RJ, Kelsey G, Wilkinson LS (2004) Expression patterns of the novel imprinted genes Nap1l5 and Peg13 and their non-imprinted host genes in the adult mouse brain. Gene Expr Patterns 4:741–747. doi:10.1016/j.modgep.2004.03.008

    Article  CAS  PubMed  Google Scholar 

  70. Cruz C, Ventura F, Bartrons R, Rosa JL (2001) HERC3 binding to and regulation by ubiquitin. FEBS Lett 488:74–80. doi:10.1016/S0014-5793(00)02371-1

    Article  CAS  PubMed  Google Scholar 

  71. Hochrainer K, Kroismayr R, Baranyi U et al (2008) Highly homologous HERC proteins localize to endosomes and exhibit specific interactions with hPLIC and Nm23B. Cell Mol Life Sci 65:2105–2117. doi:10.1007/s00018-008-8148-5

    Article  CAS  PubMed  Google Scholar 

  72. Kleijnen MF, Shih AH, Zhou P et al (2000) The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell 6:409–419

    Article  CAS  PubMed  Google Scholar 

  73. Hochrainer K, Pejanovic N, Olaseun VA et al (2015) The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation. Nucleic Acids Res 43:9889–9904. doi:10.1093/nar/gkv1064

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rodriguez CI, Stewart CL (2007) Disruption of the ubiquitin ligase HERC4 causes defects in spermatozoon maturation and impaired fertility. Dev Biol 312:501–508. doi:10.1016/j.ydbio.2007.09.053

    Article  CAS  PubMed  Google Scholar 

  75. Zhou H, Shi R, Wei M et al (2013) The expression and clinical significance of HERC4 in breast cancer. Cancer Cell Int 13:113. doi:10.1186/1475-2867-13-113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zeng W-L, Chen Y-W, Zhou H et al (2015) Expression of HERC4 in lung cancer and its correlation with clinicopathological parameters. Asian Pac J Cancer Prev 16:513–517

    Article  PubMed  Google Scholar 

  77. Aerne BL, Gailite I, Sims D, Tapon N (2015) Hippo stabilises its adaptor salvador by antagonising the HECT ubiquitin ligase Herc4. PLoS ONE 10:e0131113. doi:10.1371/journal.pone.0131113

    Article  PubMed  PubMed Central  Google Scholar 

  78. Mitsui K, Nakanishi M, Ohtsuka S et al (1999) A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins. Biochem Biophys Res Commun 266:115–122. doi:10.1006/bbrc.1999.1777

    Article  CAS  PubMed  Google Scholar 

  79. Dastur A, Beaudenon S, Kelley M et al (2006) Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells. J Biol Chem 281:4334–4338. doi:10.1074/jbc.M512830200

    Article  CAS  PubMed  Google Scholar 

  80. Wong JJY, Pung YF, Sze NS-K, Chin K-C (2006) 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. doi:10.1073/pnas.0600397103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kroismayr R, Baranyi U, Stehlik C et al (2004) HERC5, a HECT E3 ubiquitin ligase tightly regulated in LPS activated endothelial cells. J Cell Sci 117:4749–4756. doi:10.1242/jcs.01338

    Article  CAS  PubMed  Google Scholar 

  82. Takeuchi T, Inoue S, Yokosawa H (2006) Identification and Herc5-mediated ISGylation of novel target proteins. Biochem Biophys Res Commun 348:473–477. doi:10.1016/j.bbrc.2006.07.076

    Article  CAS  PubMed  Google Scholar 

  83. Shi H-X, Yang K, Liu X et al (2010) Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol Cell Biol 30:2424–2436. doi:10.1128/MCB.01466-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Durfee LA, Lyon N, Seo K, Huibregtse JM (2010) The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15. Mol Cell 38:722–732. doi:10.1016/j.molcel.2010.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhao C, Hsiang T-Y, Kuo R-L, Krug RM (2010) ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci USA 107:2253–2258. doi:10.1073/pnas.0909144107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Woods MW, Kelly JN, Hattlmann CJ et al (2011) Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag. Retrovirology 8:95. doi:10.1186/1742-4690-8-95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Woods MW, Tong JG, Tom SK et al (2014) Interferon-induced HERC5 is evolving under positive selection and inhibits HIV-1 particle production by a novel mechanism targeting Rev/RRE-dependent RNA nuclear export. Retrovirology 11:1–16. doi:10.1186/1742-4690-11-27

    Article  Google Scholar 

  88. Wrage M, Hagmann W, Kemming D et al (2015) Identification of HERC5 and its potential role in NSCLC progression. Int J Cancer 136:2264–2272. doi:10.1002/ijc.29298

    Article  CAS  PubMed  Google Scholar 

  89. Xue F, Higgs BW, Huang J et al (2015) HERC5 is a prognostic biomarker for post-liver transplant recurrent human hepatocellular carcinoma. J Transl Med 13:379. doi:10.1186/s12967-015-0743-2

    Article  PubMed  PubMed Central  Google Scholar 

  90. Versteeg GA, Hale BG, van Boheemen S et al (2010) Species-specific antagonism of host ISGylation by the influenza B virus NS1 protein. J Virol 84:5423–5430. doi:10.1128/JVI.02395-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oudshoorn D, van Boheemen S, Sánchez-Aparicio MT et al (2012) HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells. PLoS One. doi:10.1371/journal.pone.0029870

    PubMed  PubMed Central  Google Scholar 

  92. Ketscher L, Basters A, Prinz M, Knobeloch KP (2012) MHERC6 is the essential ISG15 E3 ligase in the murine system. Biochem Biophys Res Commun 417:135–140. doi:10.1016/j.bbrc.2011.11.071

    Article  CAS  PubMed  Google Scholar 

  93. Arimoto K, Hishiki T, Kiyonari H et al (2015) Murine Herc6 plays a critical role in protein ISGylation in vivo and has an ISGylation-independent function in seminal vesicles. J Interferon Cytokine Res 35:351–358. doi:10.1089/jir.2014.0113

    Article  CAS  PubMed  Google Scholar 

  94. Marín I (2010) Animal HECT ubiquitin ligases: evolution and functional implications. BMC Evol Biol 10:56. doi:10.1186/1471-2148-10-56

    Article  PubMed  PubMed Central  Google Scholar 

  95. Shi H-X, Yang K, Liu X et al (2010) Positive regulation of IRF3 activation by Herc5 via ISG15 modification. Mol Cell Biol. doi:10.1128/MCB.01466-09

Download references

Acknowledgments

This study was supported by a Spanish Ministerio de Ciencia e Innovación Grant BFU2011-22498 and by an Instituto de Salud Carlos III Grant RETIC, RD06/0020. T. Schneider was supported by a fellowship from the CAPES Foundation, Ministry of Education of Brazil. S. Sánchez-Tena was supported by a grant (PDJ 2013) from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain. This article is based upon work from COST Action (PROTEOSTASIS BM1307), supported by COST (European Cooperation in Science and Technology).

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Authors and Affiliations

  1. Departament de Ciències Fisiològiques II, Campus de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Susana Sánchez-Tena, Monica Cubillos-Rojas, Taiane Schneider & Jose Luis Rosa

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  1. Susana Sánchez-Tena
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  2. Monica Cubillos-Rojas
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  3. Taiane Schneider
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  4. Jose Luis Rosa
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Correspondence to Jose Luis Rosa.

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Sánchez-Tena, S., Cubillos-Rojas, M., Schneider, T. et al. Functional and pathological relevance of HERC family proteins: a decade later. Cell. Mol. Life Sci. 73, 1955–1968 (2016). https://doi.org/10.1007/s00018-016-2139-8

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  • DOI: https://doi.org/10.1007/s00018-016-2139-8

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