Compound C Reducing Interferon Expression by Inhibiting cGAMP Accumulation

Junzhong Lai; Xuan Luo; Shuoran Tian; Xing Zhang; Shanlu Huang; Hanze Wang; Qiumei Li; Shaoli Cai; Qi Chen

doi:10.3389/fphar.2020.00088

Compound C Reducing Interferon Expression by Inhibiting cGAMP Accumulation

Front Pharmacol. 2020 Feb 28:11:88. doi: 10.3389/fphar.2020.00088. eCollection 2020.

Authors

Junzhong Lai^{1

2}, Xuan Luo^{1

2}, Shuoran Tian^{1

2}, Xing Zhang^{1

2}, Shanlu Huang^{1

2}, Hanze Wang^{1

2}, Qiumei Li^{1

2}, Shaoli Cai^{1

2}, Qi Chen^{1

2}

Affiliations

¹ Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, Fuzhou, China.
² College of Life Science, Fujian Normal University Qishan Campus, Fuzhou, China.

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major DNA sensor responsible for cytosolic DNA-mediated innate immune response. Inhibition of cGAS may be an effective strategy for treating autoimmune diseases such as Aicardi-Goutieres syndrome and systemic lupus erythematosus. Compound C (also known as Dorsomorphin) has been annotated as a potent and reversible inhibitor for AMPKs as well as ALK protein kinases. Here, we report a new function of Compound C which can suppress dsDNA-dependent type I interferon induction. These effects were not dependent on the activities of AMPK proteins. In vitro assays and liquid chromatograph-mass spectrometry data show that Compound C has the capability of reducing cGAMP accumulation, suggesting that Compound C may function as a modulator involved in the cGAS-STING-mediated DNA sensing pathway. Furthermore, Compound C is able to rescue the autoimmune phenotypes in a mouse model carrying the Trex1 gene deficiency. These data demonstrate a new and inverse correlation between Compound C and type I interferon production in response to dsDNA signaling.

Keywords: DNA sensing; cGAMP; cGAS; compound C; dorsomorphin; type I interferon.