The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production.
The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production.
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DOI：
10.4049/jimmunol.1601370
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发表时间：
2017-10-15
期刊：
影响因子：
--
通讯作者：
Davis BK
中科院分区：
文献类型：
--
作者：
Tocker AM;Durocher E;Jacob KD;Trieschman KE;Talento SM;Rechnitzer AA;Roberts DM;Davis BK
胞质核苷酸的传感是I型干扰素制备的关键初始步骤。几种上游受体cGAS（环GMP-AMP合酶）之一结合胞质DNA并产生充当第二信使的双环核苷酸。这些第二信使直接与干扰素基因刺激因子（STING）结合。STING招募TANK结合激酶1（TBK 1），它作为一个关键节点，允许有效激活干扰素调节因子（IRF）以驱动抗病毒转录组。NLRC 3是最近表征的核苷酸结合结构域，富含亮氨酸重复的蛋白质（NLR），其通过抑制STING的亚细胞再分布和有效信号传导来负调节I型干扰素途径，从而钝化I型干扰素的转录。NLRC 3主要在淋巴样和髓样细胞中表达。通过酵母双杂交筛选，IQGAP 1被鉴定为NLRC 3的假定相互作用伴侣。在这里，我们表明IQGAP 1与NLRC 3相关，并可以破坏人类上皮细胞胞质溶胶中的NLRC 3：STING相互作用。此外，THP 1和HeLa细胞中IQGAP 1的敲低导致响应于胞质核酸的显著更多的干扰素-β产生。这一结果表型模仿NLRC 3缺陷型巨噬细胞和成纤维细胞，并且shRNA敲低THP 1细胞中的NLRC 3。我们的研究结果表明，IQGAP 1是一种新的调节I型干扰素的生产可能通过与NLRC 3在人类单核细胞和上皮细胞相互作用。
Sensing of cytosolic nucleotides is a critical initial step in the elaboration of type I interferon. One of several upstream receptor cGAS (cyclic-GMP-AMP synthase) binds to cytosolic DNA and generates di-cyclic nucleotides that act as secondary messengers. These secondary messengers bind directly to Stimulator of Interferon Genes (STING). STING recruits TANK binding kinase 1 (TBK1) which acts as a critical node that allows for efficient activation of interferon regulatory factors (IRFs) to drive the anti-viral transcriptome. NLRC3 is a recently characterized nucleotide-binding domain, leucine rich repeat containing protein (NLR) that negatively regulates the type I interferon pathway by inhibiting subcellular redistribution and effective signaling of STING, thus blunting the transcription of type I interferons. NLRC3 is predominantly expressed in lymphoid and myeloid cells. IQGAP1 was identified as a putative interacting partner of NLRC3 through yeast two hybrid screening. Here we show that IQGAP1 associates with NLRC3 and can disrupt the NLRC3:STING interaction in the cytosol of human epithelial cells. Furthermore, knock down of IQGAP1 in THP1 and HeLa cells causes significantly more interferon-β production in response to cytosolic nucleic acids. This result phenocopies NLRC3 deficient macrophages and fibroblasts and shRNA knock down of NLRC3 in THP1 cells. Our findings suggest IQGAP1 is a novel regulator of type I interferon production possibly via interacting with NLRC3 in human monocytic and epithelial cells.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
64.8
作者：
通讯作者：
--
DIA1和IQGAP1在细胞迁移和吞噬杯形成中相互作用。
影响因子：
7.8
作者：
Brandt, Dominique T.;Marion, Sabrina;Griffiths, Gareth;Watanabe, Takashi;Kaibuchi, Kozo;Grosse, Robert
通讯作者：
Grosse, Robert
影响因子：
11.4
作者：
Hansen, Kathrine;Prabakaran, Thaneas;Paludan, Soren R.
通讯作者：
Paludan, Soren R.
DOI：
10.4049/jimmunol.1103487
发表时间：
2012-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gorman JA;Babich A;Dick CJ;Schoon RA;Koenig A;Gomez TS;Burkhardt JK;Billadeau DD
通讯作者：
Billadeau DD