CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection.
CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection.
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DOI：
10.1016/j.celrep.2016.02.031
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发表时间：
2016-03-15
期刊：
影响因子：
8.8
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Jiang C;Zhou Z;Quan Y;Zhang S;Wang T;Zhao X;Morrison C;Heise MT;He W;Miller MS;Lin X
宿主对RNA病毒感染的反应由RNA传感器如RIG-I感测，其诱导MAVS介导的NF-κB和IRF 3活化以分别促进炎症和抗病毒反应。在这里，我们发现CARMA 3，一种先前显示介导GPCR和EGFR诱导的NF-κB活化的支架蛋白，正调控MAVS诱导的NF-κB活化。然而，我们的数据表明，CARMA 3螯合MAVS形成高分子量聚集体，从而抑制TBK 1/IRF 3活化。有趣的是，在病毒感染后NF-κB激活后，CARMA 3被靶向蛋白酶体依赖性降解，其释放MAVS以激活IRF 3。当用水泡性口炎病毒或甲型流感病毒攻击时，与野生型小鼠相比，CARMA 3缺陷型小鼠表现出减少的疾病症状，这是由于炎症减少和清除感染病毒的能力更强。总之，我们的研究揭示了CARMA 3在调节宿主抗病毒和促炎反应对RNA病毒感染的平衡中的作用。Jiang等揭示，CARMA 3是一种位于宿主基因组位点的基因，有助于宿主对RNA呼吸道病毒感染的易感性，它是通过正调节NF-κB激活但负调节IRF 3激活来控制促炎和抗病毒反应平衡的关键分子。
Host response to RNA virus infection is sensed by RNA sensors such as RIG-I, which induce MAVS-mediated NF-κB and IRF3 activation to promote inflammatory and antiviral responses, respectively. Here, we found that CARMA3, a scaffold protein previously shown to mediate NF-κB activation induced by GPCR and EGFR, positively regulates MAVS-induced NF-κB activation. However, our data suggest that CARMA3 sequesters MAVS from forming high-molecular weight aggregates, thereby suppressing TBK1/IRF3 activation. Interestingly, following NF-κB activation upon virus infection, CARMA3 is targeted for proteasome-dependent degradation, which releases MAVS to activate IRF3. When challenged with Vesicular stomatitis virus or Influenza A virus, CARMA3-deficient mice showed reduced disease symptoms compared to those of wild type mice due to less inflammation and stronger ability to clear infected virus. Together, our studies reveal the role of CARMA3 in regulating the balance of host anti-viral and pro-inflammatory responses against RNA virus infection. Jiang et al. revealed that CARMA3, a gene located in a host genomic locus that contributes to the host susceptibility to RNA respiratory virus infection, is a key molecule that controls the balance of pro-inflammatory and anti-viral responses through positively regulating NF-κB activation but negatively regulating IRF3 activation.
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影响因子：
64.8
作者：
Jiang, Fuguo;Ramanathan, Anand;Miller, Matthew T.;Tang, Guo-Qing;Gale, Michael, Jr.;Patel, Smita S.;Marcotrigiano, Joseph
通讯作者：
Marcotrigiano, Joseph
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影响因子：
64.8
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Goubau, Delphine;Schlee, Martin;Deddouche, Safia;Pruijssers, Andrea J.;Zillinger, Thomas;Goldeck, Marion;Schuberth, Christine;Van der Veen, Annemarthe G.;Fujimura, Tsutomu;Rehwinkel, Jan;Iskarpatyoti, Jason A.;Barchet, Winfried;Ludwig, Janos;Dermody, Terence S.;Hartmann, Gunther;Reis e Sousa, Caetano
通讯作者：
Reis e Sousa, Caetano
影响因子：
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影响因子：
7.7
作者：
Friedman, Constantin S.;O'Donnell, Marie Anne;Ting, Adrian T.
通讯作者：
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影响因子：
64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R