title: E3 Ubiquitin ligase RNF183 Is a Novel Regulator in Inflammatory Bowel Disease.
abstract: OBJECTIVE
  Specific members of the RING finger [RNF] protein family serve as E3 ubiquitin ligases and play important roles in the regulation of inflammation. However, their roles in the pathogenesis of inflammatory bowel disease [IBD] have not been explored.
  
  
  METHODS
  Genomic microarray of inflamed colon samples from Crohn's disease [CD] patients was performed to identify potential up-regulated genes. Expression of the identified highly up-regulated RNF183 gene was subsequently examined by quantitative reverse transcription polymerase chain reaction [qRT-PCR], western blotting and immunohistochemistry of the intestinal tissues of IBD patients and the colons of trinitrobenzene sulphonic acid [TNBS]-induced colitic mice. RNF183-mediated interaction with the NF-κB pathway and ubiquitination of IκBα were examined by siRNA, plasmid transfection, and immunoprecipitation. The miRNA predicted to target RNF183 was explored and its role in the RNF183/ NF-κB pathway was investigated.
  
  
  RESULTS
  RNF183 was up-regulated in intestinal epithelial cells in IBD patients and in colitic mice. RNF183 promoted intestinal inflammation via the activation of the NF-κB pathway by increasing the ubiquitination and degradation of IκBα. Computational analysis identified putative binding of miR-7 to RNF183. Transfection of intestinal cells with a miR-7 mimic or inhibitor confirmed its negative regulatory effect on RNF183 expression and ubiquitination of IκBα. miR-7 was down-regulated in inflamed colon tissues of IBD patients and colitic mice.
  
  
  CONCLUSIONS
  RNF183, which is negatively regulated by miR-7, is a novel regulator promoting intestinal inflammation by increasing the ubiquitination and degradation of IκBα, thereby inducing NF-κB activation. The interaction between RNF183-mediated ubiquitination and miRNA may be an important novel epigenetic mechanism in the pathogenesis of IBD.
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Yu
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chao
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Wang
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Manying
authors.initials: M
authors.lastname: Li
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Baili
authors.initials: B
authors.lastname: Chen
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: He
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China chenminhu@vip.163.com.
authors.forename: Minhu
authors.initials: M
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000201:enzymology* / Q000473:pathology; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D014302:Trinitrobenzenesulfonic Acid; D044767:Ubiquitin-Protein Ligases; C549242:MIRN7-1 microRNA, human; C549243:MIRN7 microRNA, mouse; C000620141:RNF183 protein, human; C000620142:RNF183 protein, mouse
keywords: Inflammatory bowel disease; Intestinal inflammation; NF-κB; RNF183; TNF-α; Infliximab; microRNA-7