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.

Differentiation enhances Zika virus infection of neuronal brain cells

“…To investigate the hypothesis that decreases in the relative expression of interferon-associated genes may explain increased susceptibility of RA-differentiated versus undifferentiated SH-SY5Y cells to ZIKV infection, we analyzed the transcriptome profiling data for levels of expression of interferon-stimulated genes (ISGs). We did not observe down-regulation of ISGs in differentiated cells; rather, genes associated with type I interferon signaling, such as IRF9 and STAT2, were up-regulated in RA-differentiated cells, and the only significantly down-regulated gene identified, DSCT1, was a negative regulator of type I interferon signaling 37 . This suggested that the enhanced ZIKV infection in RA-differentiated cells was not due to basal decreases in the expression of ISGs.…”

FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation

“…These findings further demonstrated that DCST1 promoted conjugation of only the K48 lysine containing ubiquitin to STAT2. This conjugation indicates that it promotes K48 ubiquitination of STAT2 (34). Although recent studies have evaluated STAT stability regulation, the molecular mechanisms and E3 ubiquitin ligase for STATs are largely unknown.…”

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

“…These proteins have been shown to be overexpressed in several types of cancer, including melanoma, gastrointestinal tumors, lymphoma, and pancreatic cancer, thereby playing an active role in cancer promotion [141][142][143][144][145][146]. Likewise, the ubiquitin ligase DCST1 is able to induce ubiquitination and degradation of STAT2, which results in hampered type I IFN signaling and has also been shown to be elevated in various cancers [147]. The small molecule inhibitors PRT4165 and A01 successfully inhibit, respectively, RNF2 and Smurf1 in vitro [148,149].…”