Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7.
Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7.
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DOI：
10.1038/s41467-021-27701-x
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发表时间：
2022-01-10
影响因子：
16.6
通讯作者：
Bowie AG
中科院分区：
文献类型：
--
作者：
Gu L;Casserly D;Brady G;Carpenter S;Bracken AP;Fitzgerald KA;Unterholzner L;Bowie AG
I型干扰素(IFN)对抗病毒反应至关重要，当调节失调时也会驱动自身免疫。在病毒感应时，单核细胞诱导一系列涉及反馈放大的干扰素β和干扰素α的产生，但这一级联反应在人类细胞中的确切调控方式尚不完全清楚。在这里，我们证明了PYHIN蛋白髓细胞核分化抗原是单核细胞诱导干扰素α所必需的。与其他PYHIN不同，这不是由于病原体感应作用，而是MNDA调控IRF7的表达，IRF7是诱导干扰素α所必需的转录因子。从机制上讲，MNDA是STAT2和RNA聚合酶II向IRF7基因启动子募集所必需的，事实上，MNDA本身在I型干扰素刺激后被募集到IRF7启动子。这些数据表明，MNDA是人髓系细胞中I型干扰素级联的关键调节因子，并揭示了人PYHIN在先天性免疫基因诱导中的新作用。干扰素反应是先天免疫反应的重要组成部分。在这里，作者暗示MNDA参与了I型干扰素对病原体感染的反应的调节。
Type I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNβ and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction. The interferon response is a critical component of the innate immune response. Here the authors implicate MNDA in the regulation of type I interferon responses to pathogen infection.