DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs.
DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs.
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DOI：
10.1126/sciimmunol.abi4493
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发表时间：
2021-12-03
影响因子：
24.8
通讯作者：
Ambati J
中科院分区：
文献类型：
--
作者：
Wang SB;Narendran S;Hirahara S;Varshney A;Pereira F;Apicella I;Ambati M;Ambati VL;Yerramothu P;Ambati K;Nagasaka Y;Argyle D;Huang P;Baker KL;Marion KM;Gupta K;Liu B;Hinton DR;Canna SW;Sallam T;Sadda SR;Kerur N;Gelfand BD;Ambati J
通过被称为炎症体的多蛋白复合体检测微生物产物是宿主抵御病原体的关键。含有4个核苷酸结合域亮氨酸重复序列(NLR)的卡片域(NLRC4)对细菌产物的反应形成一个炎症体；这需要NLR家族的凋亡抑制蛋白(NAIPS)来检测它们，NLRC4与NLRC4有物理联系。然而，与慢性非传染性疾病有关的无菌NLRC4炎性小体激活的机制仍不清楚。在这里，我们报道了促进萎缩性黄斑变性(AMD)和系统性红斑狼疮(SLE)的内源性短散在核素(SINE)RNA诱导NLRC4炎症小体激活，而不依赖NAIPS。我们发现DDX17是一个DExD/H盒RNA解旋酶，是Sine RNA的传感器，它允许由NLRC4、NLR吡咯域包含蛋白3(NLRP3)和凋亡相关的SPECK样蛋白包含卡(ASC)组成的炎症体的组装，并诱导caspase-1激活和细胞因子的释放。抑制DDX17介导的NLRC4炎性小体激活可减少SLE患者外周血单核细胞中白介素18(IL-18)的释放，从而预防AMD动物模型的视网膜变性。我们的发现揭示了一个以前未被发现的由内源性反转录转座子激活的非典型NLRC4炎症体，并为Sine RNA驱动的疾病提供了潜在的治疗靶点。DDX17感知反转录转座子RNA并激活非规范的NLRC4炎症体。
Detection of microbial products by multiprotein complexes known as inflammasomes is pivotal to host defense against pathogens. Nucleotide-binding domain leucine-rich repeat (NLR) CARD domain containing 4 (NLRC4) forms an inflammasome in response to bacterial products; this requires their detection by NLR family apoptosis inhibitory proteins (NAIPs), with which NLRC4 physically associates. However, the mechanisms underlying sterile NLRC4 inflammasome activation, which is implicated in chronic non-infectious diseases, remain unknown. Here, we report that endogenous short interspersed nuclear element (SINE) RNAs, which promote atrophic macular degeneration (AMD) and systemic lupus erythematosus (SLE), induce NLRC4 inflammasome activation independent of NAIPs. We identify DDX17, a DExD/H box RNA helicase, as the sensor of SINE RNAs that licenses assembly of an inflammasome comprising NLRC4, NLR pyrin domain-containing protein 3 (NLRP3), and apoptosis-associated speck-like protein containing CARD (ASC), and induces caspase-1 activation and cytokine release. Inhibiting DDX17-mediated NLRC4 inflammasome activation decreased interleukin-18 (IL-18) release in SLE patient peripheral blood mononuclear cells and prevented retinal degeneration in an animal model of AMD. Our findings uncover a previously unrecognized noncanonical NLRC4 inflammasome activated by endogenous retrotransposons and provide potential therapeutic targets for SINE RNA-driven diseases. DDX17 senses retrotransposon RNA and activates a noncanonical NLRC4 inflammasome.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
DOI：
10.1126/science.aac7442
发表时间：
2015-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hung T;Pratt GA;Sundararaman B;Townsend MJ;Chaivorapol C;Bhangale T;Graham RR;Ortmann W;Criswell LA;Yeo GW;Behrens TW
通讯作者：
Behrens TW
影响因子：
7.7
作者：
Cheng Y;Saville L;Gollen B;Isaac C;Belay A;Mehla J;Patel K;Thakor N;Mohajerani MH;Zovoilis A
通讯作者：
Zovoilis A
影响因子：
24.1
作者：
通讯作者：
--
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.