title: The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis.
abstract: Neddylation, the covalent attachment of ubiquitin-like protein Nedd8, of the Cullin-RING E3 ligase family regulates their ubiquitylation activity. However, regulation of HECT ligases by neddylation has not been reported to date. Here we show that the C2-WW-HECT ligase Smurf1 is activated by neddylation. Smurf1 physically interacts with Nedd8 and Ubc12, forms a Nedd8-thioester intermediate, and then catalyses its own neddylation on multiple lysine residues. Intriguingly, this autoneddylation needs an active site at C426 in the HECT N-lobe. Neddylation of Smurf1 potently enhances ubiquitin E2 recruitment and augments the ubiquitin ligase activity of Smurf1. The regulatory role of neddylation is conserved in human Smurf1 and yeast Rsp5. Furthermore, in human colorectal cancers, the elevated expression of Smurf1, Nedd8, NAE1 and Ubc12 correlates with cancer progression and poor prognosis. These findings provide evidence that neddylation is important in HECT ubiquitin ligase activation and shed new light on the tumour-promoting role of Smurf1.
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China [2] Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province 116044, China [3].
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China [2].
authors.forename: Minghua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China [2].
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Guichun
authors.initials: G
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Clinical Pharmacy, Center of Pharmacy, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chai
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.affiliation: School of Life Sciences, Xiamen University, Xiamen, Fujian Province 361102, China.
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China [2] Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province 116044, China.
authors.forename: Lingqiang
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D000075687:NEDD8 Protein; D009368:Neoplasm Transplantation; D011379:Prognosis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics* / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D029701:Saccharomyces cerevisiae Proteins; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C477008:SENP8 protein, human; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C469287:RSP5 protein, S cerevisiae; C000596156:UBE2M protein, human