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: Jun-Bao Fan, Sayuri Miyauchi-Ishida, Kei-ichiro Arimoto, Dan Liu, Ming Yan, Chang-Wei Liu, Balázs Győrffy, Dong-Er Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 46 Pg. 14313-8 (Nov 17 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26515094 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interferon Type I
• Lipopolysaccharides
• Reactive Oxygen Species
• p38 Mitogen-Activated Protein Kinases
• Ubiquitin-Activating Enzymes

Topics

• Animals
• Colitis (chemically induced, metabolism, pathology)
• Colon (metabolism, pathology)
• Interferon Type I (metabolism)
• Lipopolysaccharides (toxicity)
• Mice
• Reactive Oxygen Species (metabolism)
• Ubiquitin-Activating Enzymes (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)