Researchers Identify Key Molecular Step to Fending Off Viruses

UT Southwestern Medical Center researchers have determined how a protein that normally latches onto molecules inside cells and marks them for destruction also gives life to the body’s immune response against viruses.

The researchers discovered that a certain form of the “death” protein ubiquitin interacts with another protein, called RIG-I, but does not mark it for destruction. Instead, this form of ubiquitin binds to and activates RIG-I, which is known to trigger the body’s immune system when a virus invades a cell.

Dr. Zhijian Chen, professor of molecular biology at UT Southwestern, is senior author of the study, which is available online and in the journal Cell.

Chen and his colleagues reconstituted key elements of the human innate immune system in laboratory test tubes and found ubiquitin forms a unique chain-like structure that associates with RIG-I before RIG-I can get to work fighting viruses. The innate immune system is the body’s first generic response against invading pathogens.

“Activation of RIG-I is the first line of our immune defenses against viral infections,” said Chen, an investigator for the Howard Hughes Medical Institute at UT Southwestern. “Understanding how it comes to life is a key step in developing new approaches to antiviral therapies. Having this test-tube system could help us identify substances that enhance the body’s antiviral immunity.”

Chen said his team’s experiments mark the first time innate immunity has been recapitulated in a test tube. The findings provide one of the missing pieces in the complex puzzle of how the body fights off infection, he added.

Chen is now focusing on how activated RIG-I interacts with another protein called MAVS, also essential for immune response.

Other UT Southwestern researchers involved in the study were Dr. Wenwen Zeng and Dr. Ming Xu, both postdoctoral researchers in molecular biology; Lijun Sun and Xiang Chen, both HHMI research scientists; Xiaomo Jiang, graduate student; Dr. Fajian Hou, instructor of molecular biology; and Dr. Anirban Adkikari, former postdoctoral researcher in molecular biology.

The study was funded by the National Institutes of Health and the Welch Foundation.