Phosphoproteomics Analysis Reveals a Potential Role of CHK1 in Regulation of Innate Immunity through IRF3

Inhibitors
of checkpoint kinase 1 (CHK1), a central component of
DNA damage and cell cycle checkpoint response, represent a promising
new cancer therapy, but the global cellular functions they regulate
through phosphorylation are poorly understood. To elucidate the CHK1-regulated
phosphorylation network, we performed a global quantitative phosphoproteomics
analysis, which revealed 142 phosphosites whose phosphorylation levels
were significantly different following treatment with the CHK1 inhibitor
SCH 900776. Bioinformatics analysis identified phosphoproteins that
function in ATR–CHK1 signaling, DNA replication, and DNA repair.
Furthermore, IRF3 phosphorylation at S173 and S175 was significantly
reduced following treatment with SCH 900776. Our findings indicate
that the CHK1-dependent regulation of IRF3 phosphorylation at S173
and S175 may play a role in the induction of innate immune response
after replication stress or DNA damage, which suggests a potential
function of CHK1 in the innate immune response. Data are available
via ProteomeXchange with identifier PXD015125.

细胞周期检查点激酶1（CHK1）是DNA损伤与细胞周期检查点应答的核心组分，其抑制剂是一类颇具前景的新型癌症治疗手段，但这类抑制剂通过磷酸化调控的全局细胞功能仍不甚明晰。为阐明CHK1调控的磷酸化网络，我们开展了全局定量磷酸化蛋白质组学分析，结果显示经CHK1抑制剂SCH 900776处理后，共有142个磷酸化位点的磷酸化水平发生显著改变。生物信息学分析鉴定出参与ATR-CHK1信号通路、DNA复制及DNA修复的磷酸化蛋白质。此外，经SCH 900776处理后，干扰素调节因子3（IRF3）在S173与S175位点的磷酸化水平显著降低。本研究结果表明，CHK1依赖的IRF3 S173、S175位点磷酸化调控，可能在复制应激或DNA损伤后的先天免疫应答诱导中发挥作用，这提示CHK1在先天免疫应答中存在潜在功能。相关数据集可通过标识符为PXD015125的ProteomeXchange获取。