Herpesvirus Genome Recognition Induced Acetylation of Nuclear IFI16 Is Essential for Its Cytoplasmic Translocation, Inflammasome and IFN-β Responses.
Herpesvirus Genome Recognition Induced Acetylation of Nuclear IFI16 Is Essential for Its Cytoplasmic Translocation, Inflammasome and IFN-β Responses.
复制标题
DOI：
10.1371/journal.ppat.1005019
复制
发表时间：
2015-07
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：
Ansari MA;Dutta S;Veettil MV;Dutta D;Iqbal J;Kumar B;Roy A;Chikoti L;Singh VV;Chandran B
IL-1β和I型干扰素-β（IFN-β）分子是真核生物体内重要的炎性细胞因子，可作为天然免疫应答来对抗入侵的病原体和危险信号。最近，一种主要参与转录调控的核γ-干扰素诱导蛋白16（IFI 16）已经作为先天DNA传感器出现，其分别通过炎性体和STING激活来诱导IL-1β和IFN-β的产生。疱疹病毒（KSHV、EBV和HSV-1）附加型dsDNA基因组被IFI 16识别导致IFI 16-ASC-半胱天冬酶原-1炎性小体缔合、细胞质易位和IL-1β产生。独立于ASC，HSV-1基因组识别导致IFI 16与细胞质中的STING相互作用以诱导干扰素-β产生。然而，IFI 16-炎性小体形成、细胞质再分布和STING激活的机制尚不清楚。我们在此的研究表明，通过IFI 16识别细胞核中的疱疹病毒基因组导致其与组蛋白乙酰转移酶p300的相互作用和IFI 16乙酰化，从而导致IFI 16-ASC相互作用、炎性小体组装、与Ran-GT3的增加的相互作用、细胞质再分布、半胱天冬酶-1活化、IL-1β产生以及与STING的相互作用，这导致IRF-3磷酸化，核pIRF-3定位和干扰素-β产生。ASC和STING敲除不影响IFI 16乙酰化，表明这种修饰是炎性小体组装和STING活化的上游。在细胞质中复制的牛痘病毒不诱导核IFI 16乙酰化和胞质易位。如通过邻近连接显微镜和染色质免疫沉淀研究所揭示的，IFI 16与KSHV和HSV-1基因组物理关联，其不受乙酰化抑制的阻碍，从而表明IFI 16的乙酰化对于其核病毒基因组的先天感测不是必需的。总的来说，这些研究将IFI 16的增加的核乙酰化鉴定为细胞核中的动态必需的后基因组识别事件，其对于疱疹病毒（KSHV、EBV、HSV-1）感染期间IFI 16介导的炎性小体诱导和IFN-β产生的先天性应答是常见的。疱疹病毒在特定细胞的细胞核中建立潜伏感染，并且再活化导致核病毒dsDNA复制和感染性病毒产生。宿主先天性应答由病毒基因组及其产物的存在启动，并且核相关的IFI 16蛋白最近已作为调节炎性细胞因子和I型干扰素（IFN）产生的先天性DNA传感器出现。IFI 16识别细胞核中的疱疹病毒基因组（KSHV、EBV和HSV-1），导致IFI 16-ASC-Caspase-1炎性体复合物的形成和IL-1β的产生。细胞核中IFI 16对HSV-1基因组的识别也导致细胞质中的STING活化和IFN-β产生。然而，在病毒基因组的核识别之后，IFI 16如何启动炎性小体组装并激活细胞质中的STING尚不清楚。我们表明，细胞核中的疱疹病毒基因组识别IFI 16导致与组蛋白乙酰转移酶-p300和IFI 16乙酰化的相互作用，这对于细胞核中的炎性小体组装和细胞质易位、细胞质中STING的激活和IFN-β的产生是必需的。这些研究提供了对分别导致IL-1β和IFN-β产生的先天性炎性小体组装和STING活化反应途径的共同分子机制的深入了解。
The IL-1β and type I interferon-β (IFN-β) molecules are important inflammatory cytokines elicited by the eukaryotic host as innate immune responses against invading pathogens and danger signals. Recently, a predominantly nuclear gamma-interferon-inducible protein 16 (IFI16) involved in transcriptional regulation has emerged as an innate DNA sensor which induced IL-1β and IFN-β production through inflammasome and STING activation, respectively. Herpesvirus (KSHV, EBV, and HSV-1) episomal dsDNA genome recognition by IFI16 leads to IFI16-ASC-procaspase-1 inflammasome association, cytoplasmic translocation and IL-1β production. Independent of ASC, HSV-1 genome recognition results in IFI16 interaction with STING in the cytoplasm to induce interferon-β production. However, the mechanisms of IFI16-inflammasome formation, cytoplasmic redistribution and STING activation are not known. Our studies here demonstrate that recognition of herpesvirus genomes in the nucleus by IFI16 leads into its interaction with histone acetyltransferase p300 and IFI16 acetylation resulting in IFI16-ASC interaction, inflammasome assembly, increased interaction with Ran-GTPase, cytoplasmic redistribution, caspase-1 activation, IL-1β production, and interaction with STING which results in IRF-3 phosphorylation, nuclear pIRF-3 localization and interferon-β production. ASC and STING knockdowns did not affect IFI16 acetylation indicating that this modification is upstream of inflammasome-assembly and STING-activation. Vaccinia virus replicating in the cytoplasm did not induce nuclear IFI16 acetylation and cytoplasmic translocation. IFI16 physically associates with KSHV and HSV-1 genomes as revealed by proximity ligation microscopy and chromatin-immunoprecipitation studies which is not hampered by the inhibition of acetylation, thus suggesting that acetylation of IFI16 is not required for its innate sensing of nuclear viral genomes. Collectively, these studies identify the increased nuclear acetylation of IFI16 as a dynamic essential post-genome recognition event in the nucleus that is common to the IFI16-mediated innate responses of inflammasome induction and IFN-β production during herpesvirus (KSHV, EBV, HSV-1) infections. Herpesviruses establish a latent infection in the nucleus of specific cells and reactivation results in the nuclear viral dsDNA replication and infectious virus production. Host innate responses are initiated by the presence of viral genomes and their products, and nucleus associated IFI16 protein has recently emerged as an innate DNA sensor regulating inflammatory cytokines and type I interferon (IFN) production. IFI16 recognizes the herpesvirus genomes (KSHV, EBV, and HSV-1) in the nucleus resulting in the formation of the IFI16-ASC-Caspase-1 inflammasome complex and IL-1β production. HSV-1 genome recognition by IFI16 in the nucleus also leads to STING activation in the cytoplasm and IFN-β production. However, how IFI16 initiates inflammasome assembly and activates STING in the cytoplasm after nuclear recognition of viral genome are not known. We show that herpesvirus genome recognition in the nucleus by IFI16 leads to interaction with histone acetyltransferase-p300 and IFI16 acetylation which is essential for inflammasome assembly in the nucleus and cytoplasmic translocation, activation of STING in the cytoplasm and IFN-β production. These studies provide insight into a common molecular mechanism for the innate inflammasome assembly and STING activation response pathways that result in IL-1β and IFN-β production, respectively.
登录
查看更多内容
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
64.8
作者：
Qu, Yan;Misaghi, Shahram;Dixit, Vishva M.
通讯作者：
Dixit, Vishva M.
影响因子：
6.7
作者：
Johnson KE;Bottero V;Flaherty S;Dutta S;Singh VV;Chandran B
通讯作者：
Chandran B
影响因子：
30.3
作者：
Kerur N;Veettil MV;Sharma-Walia N;Bottero V;Sadagopan S;Otageri P;Chandran B
通讯作者：
Chandran B
接头 ASC 的磷酸化充当分子开关，控制斑点状聚集体的形成和炎症小体活性。
影响因子：
30.5
作者：
Hara H;Tsuchiya K;Kawamura I;Fang R;Hernandez-Cuellar E;Shen Y;Mizuguchi J;Schweighoffer E;Tybulewicz V;Mitsuyama M
通讯作者：
Mitsuyama M