title: Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation.
abstract: Type I IFNs have broad activity in tissue inflammation and malignant progression that depends on the expression of IFN-stimulated genes (ISGs). ISG15, one such ISG, can form covalent conjugates to many cellular proteins, a process termed "protein ISGylation." Although type I IFNs are involved in multiple inflammatory disorders, the role of protein ISGylation during inflammation has not been evaluated. Here we report that protein ISGylation exacerbates intestinal inflammation and colitis-associated colon cancer in mice. Mechanistically, we demonstrate that protein ISGylation negatively regulates the ubiquitin-proteasome system, leading to increased production of IFN-induced reactive oxygen species (ROS). The increased cellular ROS then enhances LPS-induced activation of p38 MAP kinase and the expression of inflammation-related cytokines in macrophages. Thus our studies reveal a regulatory role for protein ISGylation in colonic inflammation and its related malignant progression, indicating that targeting ubiquitin-activating enzyme E1 homolog has therapeutic potential in treating inflammatory diseases.
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Jun-Bao
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Sayuri
authors.initials: S
authors.lastname: Miyauchi-Ishida
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Arimoto
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Chang-Wei
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Hungarian Academy of Sciences, Research Centre for Natural Sciences, Momentum Cancer Biomarker Research Group, Budapest, H-1117, Hungary; Second Department of Pediatrics, Semmelweis University, Budapest, H-1094, Hungary; Hungarian Academy of Sciences and Semmelweis University, Pediatrics and Nephrology Research Group, Budapest, H-1085, Hungary;
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093; Department of Pathology and Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 d7zhang@ucsd.edu.
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D007370:Interferon Type I / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007370:Interferon Type I; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D044764:Ubiquitin-Activating Enzymes
keywords: ISGylation; cancer; cytokine; inflammation; ubiquitylation