Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

Jun Bao Fan, Sayuri Miyauchi-Ishida, Kei Ichiro Arimoto, Dan Liu, Ming Yan, Chang Wei Liu, Balázs Gyorffy, Dong Er Zhang

Research output: Contribution to journalArticle

15 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)14313-14318
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
Publication statusPublished - Nov 17 2015



  • Cancer
  • Cytokine
  • ISGylation
  • Inflammation
  • Ubiquitylation

ASJC Scopus subject areas

  • General

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