BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-β Responses.
BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-β Responses.
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DOI：
10.1371/journal.ppat.1005030
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Chandran B
中科院分区：
文献类型：
--
作者：
Dutta D;Dutta S;Veettil MV;Roy A;Ansari MA;Iqbal J;Chikoti L;Kumar B;Johnson KE;Chandran B
天然免疫系统模式识别受体是识别各种病原体或危险相关分子模式的第一道防线，通过调节促炎细胞因子如IL-1β、IL-18或干扰素β(干扰素-β)的产生而引发防御。Nod样受体(NLRs)和AIM2样受体(ALR)是包括DNA在内的外源分子的细胞质炎症体感受器。IFI16是一种不依赖于序列的天然核感受器，它识别感染细胞核中的疱疹病毒如KSHV、EBV和HSV-1的外体dsDNA基因组，与asc和proaspase1形成炎症体复合体，并重新定位到细胞质中，导致caspase-1和IL-1β的产生。在单纯疱疹病毒1型感染过程中，IFI16也通过胞质刺痛-β-IRF3途径诱导干扰素-IRF3。到目前为止，IFI16是直接识别外源DNA还是利用其他宿主蛋白(S)尚不清楚。在这里，我们证明了作为DNA损伤修复传感器和转录调节因子的BRCA1与IFI16在宿主细胞核中是复杂的，并且在从头感染KSHV、EBV和HSV-1以及在潜伏的KSHV或EBV感染过程中，它们的相关性随着核病毒基因组的存在而增加，但不是通过博莱霉素和痘苗病毒胞浆dsDNA诱导的DNA损伤反应(DDR)。BRCA1是触发的IFI16-炎症体的一个组成部分，在基因组识别后与IFI16-炎症体一起移位到细胞质中。缺失BRCA1基因会导致IFI16病毒基因组关联、炎症体组装、IFI16细胞质定位以及Caspase-1和IL-1β的产生。在新生KSHV和HSV-1感染过程中，BRCA1的缺失也破坏了胞质内IFI16-STING相互作用、下游IRF3的磷酸化、pIRF3的核转位和干扰素-β的产生。这些发现表明，BRCA1通过促进IFI16对核外源DNA的感知，促进IFI16-炎性小体的组装和细胞质分布，导致IL-1β的形成，以及通过IFI16-STING、Tbk1和IRF3通过细胞质信号诱导干扰素-β，发挥着迄今未知的先天免疫调节作用。包括病毒在内的病原体对宿主细胞的入侵是由模式识别受体感知的，从而激发宿主的天然防御，如形成多蛋白炎症体复合体，通过细胞质刺痛分子产生炎性IL-1β和IL-18细胞因子，以及产生干扰素-β。我们已经证明，疱疹病毒(KSHV、EBV和HSV-1)的核上体病毒DNA基因组可以被核驻留的IFI16蛋白感知，从而形成IFI16-ASC-proaspase-1炎症体复合体。在这里，我们表明BRCA1通过核内的IFI16促进病毒DNA的感知，并且是触发的IFI16-ASC-proaspase-1炎症体的一个组成部分。IFI16和BRCA1在细胞核中以复合体形式存在，在KSHV、EBV或HSV-1基因组存在时，它们的关联性增加，但不受DNA损伤反应或痘苗病毒胞质dsDNA的影响。缺失BRCA1会导致IFI16与基因组的结合、IFI16胞浆易位、IL-1β的产生、IFI16与STIN的相互作用、IRF3磷酸化、pIRF3核易位和干扰素-β的诱导。综上所述，这些结果证明了BRCA1在病毒DNA的先天感知以及随后诱导炎症小体和干扰素-β反应中的关键和新的作用。
The innate immune system pattern recognition receptors (PRR) are the first line of host defenses recognizing the various pathogen- or danger-associated molecular patterns and eliciting defenses by regulating the production of pro-inflammatory cytokines such as IL-1β, IL-18 or interferon β (IFN-β). NOD-like receptors (NLRs) and AIM2-like receptors (ALRs) are cytoplasmic inflammasome sensors of foreign molecules, including DNA. IFI16, a sequence-independent nuclear innate sensor ALR, recognizes episomal dsDNA genomes of herpes viruses such as KSHV, EBV, and HSV-1 in the infected cell nuclei, forms an inflammasome complex with ASC and procaspase1, and relocates into the cytoplasm leading into Caspase-1 and IL-1β generation. IFI16 also induces IFN-β during HSV-1 infection via the cytoplasmic STING-TBK1-IRF3 pathway. Thus far, whether IFI16 recognizes foreign DNA directly or utilizes other host protein(s) is unknown. Here, we demonstrate that BRCA1, a DNA damage repair sensor and transcription regulator, is in complex with IFI16 in the host cell nucleus, and their association increases in the presence of nuclear viral genomes during de novo KSHV, EBV and HSV-1 infection, and in latent KSHV or EBV infection, but not by DNA damage responses (DDR) induced by bleomycin and vaccinia virus cytoplasmic dsDNA. BRCA1 is a constituent of the triggered IFI16-inflammasome and is translocated into the cytoplasm after genome recognition along with the IFI16-inflammasome. The absence of BRCA1 abrogated IFI16-viral genome association, inflammasome assembly, IFI16 cytoplasmic localization, and Caspase-1 and IL-1β production. The absence of BRCA1 also abolished the cytoplasmic IFI16-STING interaction, downstream IRF3 phosphorylation, nuclear translocation of pIRF3 and IFN-β production during de novo KSHV and HSV-1 infection. These findings highlight that BRCA1 plays a hitherto unidentified innate immunomodulatory role by facilitating nuclear foreign DNA sensing by IFI16, subsequent assembly and cytoplasmic distribution of IFI16-inflammasomes leading into IL-1β formation and the induction of IFN-β via cytoplasmic signaling through IFI16-STING, TBK1 and IRF3. Invasion of a host cell by pathogens, including viruses, is sensed by pattern-recognition receptors resulting in the elicitation of the host innate defenses such as the formation of multi-protein inflammasome complexes, inflammatory IL-1β and IL-18 cytokine production and interferon-β production via the cytoplasmic STING molecule. We have shown that nuclear episomal viral DNA genomes of herpes viruses (KSHV, EBV and HSV-1) are sensed by the nuclear resident IFI16 protein, resulting in the formation of the IFI16-ASC-procaspase-1 inflammasome complex. Here, we show that BRCA1 promotes viral DNA sensing by IFI16 in the nucleus and is a constituent of the triggered IFI16-ASC-procaspase-1 inflammasome. IFI16 and BRCA1 are in complex in the nucleus and their association increases in the presence of KSHV, EBV or HSV-1 genomes, but not by the DNA damage response or vaccinia virus cytoplasmic dsDNA. The absence of BRCA1 results in abrogated IFI16-genome association, IFI16 cytoplasmic translocation, IL-1β production, IFI16 interaction with STING, IRF3 phosphorylation, pIRF3 nuclear translocation, and IFN-β induction. Taken together, these results demonstrate a crucial and novel role of BRCA1 in the innate sensing of viral DNA and subsequent induction of the inflammasome and interferon-β responses.
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