Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Sci Immunol. 2021 Dec 3;6(66):eabi4493. doi: 10.1126/sciimmunol.abi4493.
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 noninfectious 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, and apoptosis-associated speck-like protein–containing CARD and induces caspase-1 activation and cytokine release. Inhibiting DDX17-mediated NLRC4 inflammasome activation decreased interleukin-18 release in peripheral blood mononuclear cells of patients with SLE 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.
多蛋白复合物（称为炎性体）检测已知的微生物产物对于宿主防御病原体至关重要。核苷酸结合域富含亮氨酸重复序列（NLR）CARD 结构域包含 4（NLRC4）作为炎性体对细菌产物作出反应；这需要它们被 NLR 家族凋亡抑制蛋白（NAIPs）检测，NLRC4 与 NAIPs 物理相关。然而，在慢性非传染性疾病中涉及的无菌 NLRC4 炎性体激活的机制仍然未知。在这里，我们报告内源性短散布核元件（SINE）RNA 可诱导 NLRC4 炎性体激活，而无需 NAIPs。我们确定 DDX17，一种 DExD/H 框 RNA 解旋酶，作为 SINE RNA 的传感器，它允许包含 NLRC4、NLR 吡喃结构域包含蛋白 3 和凋亡相关斑点样蛋白包含 CARD 的炎性体组装，并诱导半胱天冬酶-1 的激活和细胞因子的释放。抑制 DDX17 介导的 NLRC4 炎性体激活可减少 SLE 患者外周血单个核细胞中白细胞介素-18 的释放，并可预防 AMD 动物模型中的视网膜变性。我们的发现揭示了一种以前未被识别的由内源性逆转录转座子激活的非典型 NLRC4 炎性体，并为 SINE RNA 驱动的疾病提供了潜在的治疗靶点。
