Compound C Reducing Interferon Expression by Inhibiting cGAMP Accumulation

• Main Authors: Junzhong Lai (Author), Xuan Luo (Author), Shuoran Tian (Author), Xing Zhang (Author), Shanlu Huang (Author), Hanze Wang (Author), Qiumei Li (Author), Shaoli Cai (Author), Qi Chen (Author)
• Format: Book
• Published: Frontiers Media S.A., 2020-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

1663-9812
10.3389/fphar.2020.00088