Researchers at the Keck School of Medicine of USC have discovered the mechanism by which the body turns off the production of interferon I, a protein that enables cells to communicate about detecting and fighting viruses.
The findings, which appeared in the journal Molecular Cell, eventually could lead to treatments for life-threatening infections and better understanding of autoimmune diseases.
Kyung-Soo Inn, a Keck School of Medicine postdoctoral fellow in microbiology and molecular immunology, was the primary researcher for the study, which was directed by Jae Jung, Fletcher Jones Professor and chair of the Department of Molecular Microbiology and Immunology.
Other contributors included Michaela Gack, a faculty member of Harvard Medical School, and researchers led by professor Kazuhiro Iwai of Osaka University in Japan. Study findings built upon an earlier investigation of interferon activation conducted by Gack, a former Ph.D. student in Jung’s lab.
Inn explained that when the immune system detects a viral infection, an antiviral signaling mechanism is activated: Retinoic acid inducible gene I (RIG-I) detects the virus signature and turns on intracellular communication to produce interferon.
Interferon then tells uninfected neighboring cells that there is an infection nearby, prompting them to produce hundreds of antiviral genes to combat it.
In a 2007 study, Gack found that tripartite motif-containing protein 25 (TRIM25) acts as a turn-on switch in the antiviral process by triggering the addition of ubiquitin, a small regulatory protein found in all tissues, to RIG-I.
“I thought there also ought to be a negative regulator to remove ubiquitin from the RIG-I and deactivate the virus sensor so that it can’t turn on interferon, simply a ‘what goes up must come down’ in innate immune activation.” Inn said. “Interferon needs to be turned off quickly because high levels of it can induce autoimmune disease and cell death.”
The study by Inn and his collaborators discovered that linear ubiquitin assembly complex (LUBAC), a grouping of proteins, can inhibit the addition of ubiquitin to RIG-I and thereby stop the release of interferon.
“We found that TRIM25 and LUBAC counteract each other to maintain a balanced level of interferon signaling,” he said.
Inn noted that interferon usually is turned on within several hours of cells being infected by a virus and stays on for about 12 hours before declining.
“If we can interfere with the action of LUBAC, we can induce higher, more prolonged interferon production, which could help if there is a life-threatening infection, even though there may be some side effects from the interferon,” he said. “Another possibility is that in some autoimmune diseases, where there are higher levels of interferon than normal, we can check whether those patients have a problem with their LUBAC.”
Inn is among those who are examining the signaling mechanisms of viruses, seeking to understand how they work and can be stopped.
He currently is investigating the virus that causes Kaposi’s sarcoma, a cancerous tumor, which can involve the skin, lungs, gastrointestinal tract and other organs. It most often appears in patients with AIDS or those who have had organ transplants.
Inn is studying whether RIG-I can recognize the Kaposi’s sarcoma virus and if the virus can stop the activation of interferon.