通过激酶组全 siRNA 筛选鉴定 DAPK1 通过磷酸化依赖性反馈抑制 RIG-I。
Phosphorylation-Dependent Feedback Inhibition of RIG-I by DAPK1 Identified by Kinome-wide siRNA Screening.
机构信息
Research Group "Dynamics of early viral infection and the innate antiviral response," Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department for Infectious Diseases, Molecular Virology, Research Group "Dynamics of early viral infection and the innate antiviral response," Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
Department for Infectious Diseases, Molecular Virology, Research Group "Dynamics of early viral infection and the innate antiviral response," Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
出版信息
Mol Cell. 2017 Feb 2;65(3):403-415.e8. doi: 10.1016/j.molcel.2016.12.021. Epub 2017 Jan 26.
Cell-autonomous induction of type I interferon must be stringently regulated. Rapid induction is key to control virus infection, whereas proper limitation of signaling is essential to prevent immunopathology and autoimmune disease. Using unbiased kinome-wide RNAi screening followed by thorough validation, we identified 22 factors that regulate RIG-I/IRF3 signaling activity. We describe a negative-feedback mechanism targeting RIG-I activity, which is mediated by death associated protein kinase 1 (DAPK1). RIG-I signaling triggers DAPK1 kinase activation, and active DAPK1 potently inhibits RIG-I stimulated IRF3 activity and interferon-beta production. DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation.
细胞自主诱导 I 型干扰素必须受到严格调控。快速诱导是控制病毒感染的关键，而适当限制信号传递对于防止免疫病理和自身免疫性疾病至关重要。我们使用无偏见的激酶组 RNAi 筛选，然后进行彻底的验证，鉴定了 22 种调节 RIG-I/IRF3 信号活性的因子。我们描述了一种针对 RIG-I 活性的负反馈机制，该机制由凋亡相关蛋白激酶 1（DAPK1）介导。RIG-I 信号触发 DAPK1 激酶的激活，而活性 DAPK1 强烈抑制 RIG-I 刺激的 IRF3 活性和干扰素-β的产生。DAPK1 在体外对 RIG-I 进行磷酸化，磷酸化位点既有先前报道的，也有其他的，这些位点限制了 5'ppp-dsRNA 的感应，几乎完全抑制了 RIG-I 的激活。
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