2014 Distinguished Innovator Awardee
Roles of the cGAS pathway in lupus
The Study and What It Means to Patients
“We have discovered an essential new process that alerts the immune system to viruses by sensing the presence of ‘foreign DNA within cells’. With our Distinguished Innovator award, we will explore our hypothesis that this pathway malfunctions in lupus, causing the immune system to attack its own DNA.”
Lupus patients commonly have elevated levels of interferon, proteins that signal the presence of pathogens such as viruses, parasites or bacteria, and autoantibodies, antibodies which mistakenly attack good cells, that are targeted at DNA. This suggests that abnormal stimulation of the interferon pathway – which helps regulate the immune system’s response to foreign invaders – plays a significant role in lupus. Recently, our lab discovered a new enzyme called cGAS. When activated by attaching to DNA, the enzyme starts a chain of events that eventually induces the production of interferons and other molecules that stimulate the immune system. We propose that activation of the cGAS pathway may be a major cause of lupus and that compounds that block cGAS activity may be developed into effective drugs for the treatment of lupus. Our proposed study aims to determine if cGAS could be used as a potential target for a new lupus medicine.
Aberrant activation of the type-I interferon (IFN) pathway is a hallmark of systemic autoimmune diseases, including systemic lupus erythematosus (SLE), Sjogren’s syndrome and Aicardi Goutieres Syndrome (AGS). How IFNs and other inflammatory cytokines are abnormally induced in these diseases is still not well understood. Recently, our lab discovered the cytosolic DNA sensor cGAS that activates the type-I interferon pathway in response to microbial or self DNA. cGAS is an enzyme that is activated upon its binding to DNA. The activated cGAS catalyzes the synthesis of cyclic-GMP-AMP (cGAMP), which functions as a second messenger that activates the adaptor protein STING. STING in turn activates the protein kinases IKK and TBK1, which activate the transcription factors NF-?B and IRF3, respectively, to induce IFNs and other immune stimulatory molecules. Our genetic experiments using cGAS-deficient mice have demonstrated the essential role of cGAS in immune responses to DNA viruses and retroviruses. Moreover, our recent data show that cGAS is required for the development of some autoimmune diseases caused by self DNA. These results suggest that aberrant activation of the cGAS-STING pathway may cause autoimmune diseases including SLE. The goal of this proposal is to investigate the role of cGAS in lupus development.