11:10pm Monday 20 January 2020

Researchers Identify Mechanism to Control Immune Signaling; Study Points to Treatment of Inflammatory Diseases

The findings are published in the October edition of the journal Cell.

“Our scientific findings could lead to translational research and the generation of new drugs and therapeutics that could stop chronic inflammatory processes,” said senior author Glen N. Barber, Ph.D., professor and Chair of Cell Biology and Associate Director for Basic Research at the Sylvester Comprehensive Cancer Center.

Barber leads a Miller School research team that has been studying cellular defenses against viruses, bacteria and other pathogens. Molecular sensors detect these invaders and activate pathways that signal the cell to produce anti-bacterial and anti-viral proteins, and to attract pathogen-fighting white blood T-cells that play a key role in the body’s immune system.

For example, interferons (IFNs) are secreted from the cell in response to virus infection and trigger the expression of genes that can exert potent antiviral and antitumor activity. In 2008, Barber found that a molecule referred to as STING (STimulator of IFN Genes) was essential for producing interferon in response to a variety of DNA pathogens. In two follow-up studies published in 2012, however, Barber showed that chronic activation of the STING pathway can lead to lethal inflammatory disease. Earlier in the year, Barber’s lab also published information on the molecular mechanisms of STING function in the journal Molecular Cell.

“Our team’s work has shown that the body needs a rapid STING response in order to fight infections,” Barber said. “But that response needs to be deactivated after nine to 12 hours or it over-stimulates the immune system.”

Barber’s latest study points to ways to turn off that STING pathway. The study, “Cyclic Dinucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling,” was published in Cell with Department of Cell Biology co-authors Hiroyasu Konno, Ph.D., postdoctoral associate, and Keiko Konno, M.S., research associate.

The Cell study notes that activation of cyclic dinucleotides (CDN) plays a key role in the normal activation of the immune system response. “However, these dinucleotides also serve to trigger a negative feedback control loop so the immune system returns to normal,” Barber said. “If the STING response is not turned off, it could result in chronic inflammatory disease.”

In addition to studying the body’s inflammatory response, Barber and his researchers are continuing their studies on STING activity and cellular mechanisms involved in defending against cancer or other diseases. “Being able to stimulate the STING pathway for a transient period could lead to more effective treatments for cancerous tumors,” he said. “It could also result in more powerful vaccines to help prevent diseases in the future.”

University of Miami

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