RESUMO
Cyclic GMP-AMP synthase (cGAS) functions as a key sensor for microbial invasion and cellular damage by detecting emerging cytosolic DNA. Here, we report that GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid-phase condensation state. Using high-resolution microscopy, we show that in resting cells, cGAS exhibits particle-like morphological characteristics, which are markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre-condensed cGAS undergoes liquid-liquid phase separation (LLPS) more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminishes DNA-induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, previously reported to form condensates with cGAS, does not activate cGAS. Accordingly, we find that DNA - but not RNA - treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study shows that the primary condensation state of cGAS is critical for its rapid response to DNA.
Assuntos
DNA Helicases , Nucleotidiltransferases , Proteínas de Ligação a Poli-ADP-Ribose , RNA Helicases , Proteínas com Motivo de Reconhecimento de RNA , DNA/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/genética , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/genética , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Grânulos de EstresseRESUMO
BACKGROUND: Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is critical for cytosolic DNA-sensing and the subsequent immune responses. The inappropriate activation of this pathway leads to DNA-induced autoimmune response. Understanding the precise regulation of cGAS-STING pathway is important for developing therapeutics to treat several autoimmune diseases caused by self-DNA. RESULTS: We report that Meloxicam (MXC) inhibits intracellular DNA-, but not RNA-induced immune responses. We find that MXC inhibits the phosphorylation of STING by examining in different cells with various DNA stimulations. We further find that MXC significantly dampens the expression levels of interferon-stimulated genes (ISGs) by using DNA 3' repair exonuclease 1 (TREX1)-deficient cell, an experimental model for self-DNA-induced autoimmune disease. Importantly, we demonstrate that MXC could promote the survival in Trex1-/- mouse model for Aicardi-Goutières syndrome (AGS). CONCLUSIONS: Our study identified a non-steroidal anti-inflammatory drug, MXC, that exhibits potential effect in treating the autoimmunity caused by self-DNA.