Researchers from Virginia Commonwealth University (VCU) Massey Cancer Center have discovered a new signaling pathway in sterile inflammation that could impact the treatment of diseases such as cancer, multiple sclerosis and rheumatoid arthritis. Their findings offer insight into the role that activation of interferon-regulatory factor 1 (IRF1), a protein that functions as a transcriptional activator of a variety of target genes, plays in the production of chemokines and the recruitment of mononuclear cells to sites of sterile inflammation.
Although it has been shown that interleukin 1 (IL-1) induces the expression of IRF1, the biological importance of this was uncertain. In this study, recently published in the journal Nature Immunology, investigators Tomasz Kordula, Ph.D., and Sarah Spiegel, Ph.D., members of the Cancer Cell Signaling research program at Massey and professors in the Department of Biochemistry and Molecular Biology at the VCU School Medicine, found a new signaling pathway that links IL-1 to IRF1 in sterile inflammation.
IL-1, a key regulator of sterile inflammation, governs immune and inflammatory responses and has an important role in autoinflammatory diseases. IL-1 signaling triggers a process called polyubiquitination. Polyubiquitination is important to a variety of cellular functions. While one form of polyubiquitination has been called the “kiss of death” because it targets proteins for degradation, another form known as K63-linked polyubiquitination is important to cell signaling.
“For the first time, we found that K63-linked polyubiquitination is a mechanism of IRF1 activation,” says Kordula. “Once activated, IRF1 induces potent chemokines that recruit immune cells to sites of sterile inflammation and promote healing.”
Kordula and Spiegel, Mann T. and Sara D. Lowry Professor of Oncology and co-leader of the Cancer Cell Signaling research program at Massey and chair of the Department of Biochemistry and Molecular Biology at the VCU School of Medicine, previously discovered a link between chronic inflammation and cancer.
“As IRF1 affects the development of autoinflammatory diseases, targeting this previously unrecognized IL-1-induced cascade may be clinically important in the future,” says Kordula. “Our next steps are to develop cell-specific, conditional IRF1 animal models in order to determine the cell type(s) responsible for the production of IRF1-mediated chemokines in the brain.”
Kordula and Spiegel collaborated on this research with Kazuaki Takabe, M.D., Ph.D., F.A.C.S., member of the Cancer Cell Signaling research program at Massey and associate professor in the Department of Surgery at the VCU School of Medicine; Kuzhuvelil B. Harikumar, Ph.D., Jessie W. Yester, Ph.D., Michael J. Surace, Ph.D., Clement Oyeniran, Ph.D., Megan M. Price, Ph.D., Wei-Ching Huang, Ph.D., Nitai C. Hait, Ph.D., Jeremy C. Allegood, Ph.D., Reetika Bhardwaj and Sheldon Milstien, Ph.D., from the Department of Biochemistry and Molecular Biology at the VCU School of Medicine; Akimitsu Yamada, Ph.D., from the Department of Surgery at the VCU School of Medicine; Xiangqian Kong, Ph.D., and Cheng Luo, Ph.D., from the Chinese Academy of Sciences; and Helen M. Lazear, Ph.D., and Michael S. Diamond, M.D., Ph.D., from Washington University School of Medicine.
This research was supported by National Institutes of Health (NIH) grants 1R01AI093718, 5R37GM043880, 1U19AI077435, and R01CA160688; grant 5P30NS047463 supporting the VCU Microscopy Facility; VCU Massey Cancer Center’s National Cancer Institute Cancer Center Support Grant P30 CA 016059; and grant 91029704 from the National Natural Science Foundation of China.
K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5. Nature Immunology (2014) doi:10.1038/ni.2810 Published online 26 January 2014