Divergent regulation of STING-mediated innate immune responses by CBP and p300

Abstract

Dysregulation of cGAS-STING pathway contributes to various disorders, including autoimmunity, infectious diseases and cancer. Transcription factors, particularly IRF3 which presumably recruits CBP/p300 as transcription coactivators, drive innate immune responses to STING activation. Here we show that CBP/p300 inhibitors (p300i) boost, not repress as expected, the cGAMP-induced transcription of innate immune genes. Mechanistically, p300i and a CBP/p300 degrader markedly enhance the cGAMP-induced IRF3 phosphorylation and slightly increase NF-{kappa}B activation. Furthermore, cGAMP stimulation increases the presence of p300, not CBP, in the cytoplasm to interrupt interactions between TBK1 and IRF3. Conversely, p300i enhances TBK1-IRF3 interactions, resulting in higher IRF3 phosphorylation. After STING activation, CBP, not p300, is recruited to chromatin along with IRF3 and is coupled with H3K27ac upregulation. At later stages of STING activation, nearly all CBP and p300 are detached from chromatin, which is associated with global histone deacetylation, IRF3 chromatin eviction, and the termination of IRF3-driven transcription programs. p300i robustly enhances IRF3 chromatin engagement which consequently amplifies type 1 interferon responses to STING activation. Together, these findings suggest that CBP, not p300, acts as a transcription coactivator in the nucleus. In contrast, p300, not CBP, is a suppressor of STING signaling in the cytoplasm.