title: The ubiquitin ligase Cullin5SOCS2regulates NDR1/STK38 stability and NF-κB transactivation.
abstract: SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic profiling upon SOCS2 depletion and yield quantitative data for ~4200 proteins. Through this screen we identify a novel target of SOCS2, the serine-threonine kinase NDR1. Over-expression of SOCS2 accelerates turnover, while its knockdown stabilizes, endogenous NDR1 protein. SOCS2 interacts with NDR1 and promotes its degradation through K48-linked ubiquitination. Functionally, over-expression of SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity. Conversely, depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation. Using a SOCS2-/-mice model of colitis we show that SOCS2-deficiency is pro-inflammatory and negatively correlates with NDR1 and nuclear p65 levels. Lastly, we provide evidence to suggest that NDR1 acts as an oncogene in prostate cancer. To the best of our knowledge, this is the first report of an identified E3 ligase for NDR1. These results might explain how SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications and posits that SOCS2 induced degradation of NDR1 may act as a switch in restricting TNFα-NF-κB pathway.
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Indranil
authors.initials: I
authors.lastname: Paul
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Tanveer S
authors.initials: TS
authors.lastname: Batth
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, c/o the Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Diego
authors.initials: D
authors.lastname: Iglesias-Gato
authors.affiliation: College of Medicine and Health Sciences, Sultan Qaboos University, P.O. box 35, P.C 123, Muscat, Oman.
authors.forename: Amna
authors.initials: A
authors.lastname: Al-Araimi
authors.affiliation: College of Medicine and Health Sciences, Sultan Qaboos University, P.O. box 35, P.C 123, Muscat, Oman.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Haddabi
authors.affiliation: College of Medicine and Health Sciences, Sultan Qaboos University, P.O. box 35, P.C 123, Muscat, Oman.
authors.forename: Amira
authors.initials: A
authors.lastname: Alkharusi
authors.affiliation: College of Medicine and Health Sciences, Sultan Qaboos University, P.O. box 35, P.C 123, Muscat, Oman.|Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: College of Medicine and Health Sciences, Sultan Qaboos University, P.O. box 35, P.C 123, Muscat, Oman.
authors.forename: Fahad
authors.initials: F
authors.lastname: Zadjali
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.|Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, c/o the Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Amilcar
authors.initials: A
authors.lastname: Flores-Morales
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003092:Colitis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004795:Enzyme Stability; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human