May 19, 2020

Probing innate immunity

Manuel Ascano team validates an inhibitor of the cGAS-STING signaling pathway, which is important for cellular innate immunity against bacteria, viruses, and our own damaged DNA.

by Leigh MacMillan

The protein cGAS plays an essential role in cellular innate immunity by detecting the DNA of invading pathogens such as bacteria and viruses, or our own damaged and mislocalized DNA. Activation of the cGAS-STING signaling pathway produces a pro-inflammatory immune response, and prolonged activation of cGAS can result in lupus-like autoimmune disorders. 

Manuel Ascano, PhD, and colleagues previously identified the compound RU.521 as an inhibitor of mouse cGAS. They now demonstrate that RU.521 also potently and selectively inhibits human cGAS in cell lines and in human primary cells. They showed that RU.521 suppressed cGAS activity in a dose-dependent manner and did not suppress immune responses activated by non-DNA signals. 

The study, published May 5 in Scientific Reports, validates the use of RU.521 as a tool to assess the contribution of the cGAS-STING signaling axis in various immune responses. The compound could also serve as a chemical scaffold for the development of potential therapeutics for cGAS-related autoimmune diseases.

This research was supported in part by the National Institutes of Health (grants GM119569, HL145477).