title: Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling.
abstract: Type I interferon (IFN-I) mediated innate immune response controls virus infections by inducing the expression of interferon stimulated genes (ISGs). Although ubiquitination plays key roles in immune signaling regulation, a human genome-wide understanding of the role of E3 ubiquitin ligases in interferon mediated ISG induction is lacking. Here, we report a genome-wide profiling of the effect of ectopic expression of 521 E3 ubiquitin ligases and substrate recognition subunits encoded in the human genome (which constitutes 84.4% of all ubiquitination related genes encoded in the human genome, hereafter termed Human Ubiquitome) on IFNβ mediated induction of interferon stimulated DNA response element (ISRE) driven reporter activity. We identified 96 and 42 genes of the human ubiquitome as novel negative and positive regulators of interferon signaling respectively. Furthermore, we characterized DCST1 as a novel E3 ubiquitin ligase negatively regulating interferon response. Ectopic expression and gene silencing of DCST1 respectively attenuated and increased ISRE reporter activity. DCST1 regulated Type I interferon signaling by interacting with and promoting ubiquitination-mediated degradation of STAT2, an essential component of antiviral gene induction. In summary, this study provided a systems level view on the role of human ubiquitination associated genes in Type I interferon response.
authors: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors: Sajith
authors: S
authors: Nair
authors: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors: Pradeep
authors: P
authors: Bist
authors: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors: Neha
authors: N
authors: Dikshit
authors: Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
authors: Manoj N
authors: MN
authors: Krishnan
mesh_terms: D019295:Computational Biology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D016899:Interferon-beta / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D034741:RNA, Small Interfering; D050795:STAT2 Transcription Factor; D057149:Ubiquitinated Proteins; D016899:Interferon-beta; C000627345:DCST1 protein, human; D044767:Ubiquitin-Protein Ligases