TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response.
TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response.
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DOI：
10.1016/j.celrep.2021.108976
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发表时间：
2021-04-13
期刊：
影响因子：
8.8
通讯作者：
Karijolich J
中科院分区：
文献类型：
--
作者：
Dunker W;Ye X;Zhao Y;Liu L;Richardson A;Karijolich J
RIG-I样受体（RLR）通过识别双链RNA（dsRNA）参与自我与非自我的区分。新出现的证据表明，免疫刺激性dsRNA普遍表达，但被细胞RNA结合蛋白（RBP）破坏或隔离。TDP-43是一种与多种神经系统疾病相关的RBP，对细胞活力至关重要。在这里，我们证明了TDP-43调节免疫刺激性dsRNA的积累。免疫刺激RNA被确定为RNA聚合酶III转录本，包括7SL和Alu反转录转座子，我们证明TDP-43的RNA结合活性是防止免疫刺激所必需的。dsRNA激活RIG-I依赖性干扰素（IFN）应答，其促进坏死性凋亡。TLR途径的基因失活挽救了与TDP-43丢失相关的干扰素介导的细胞死亡。总的来说，我们的研究描述了TDP-43在防止内源性免疫刺激性dsRNA积累中的作用，并揭示了细胞基因表达控制与IFN介导的细胞死亡之间的复杂关系。Dunker等报道TDP-43参与免疫刺激性双链RNA（dsRNA）稳态的调节。TDP-43与选择的RNA聚合酶III转录物相关联，并且其损失导致它们的表达增加和RIG-I的检测。这项研究进一步加深了我们对调节免疫刺激性dsRNA积累的内在机制的理解。
RIG-I-like receptors (RLRs) are involved in the discrimination of self versus non-self via the recognition of double-stranded RNA (dsRNA). Emerging evidence suggests that immunostimulatory dsRNAs are ubiquitously expressed but are disrupted or sequestered by cellular RNA binding proteins (RBPs). TDP-43 is an RBP associated with multiple neurological disorders and is essential for cell viability. Here, we demonstrate that TDP-43 regulates the accumulation of immunostimulatory dsRNA. The immunostimulatory RNA is identified as RNA polymerase III transcripts, including 7SL and Alu retrotransposons, and we demonstrate that the RNA-binding activity of TDP-43 is required to prevent immune stimulation. The dsRNAs activate a RIG-I-dependent interferon (IFN) response, which promotes necroptosis. Genetic inactivation of the RLR-pathway rescues the interferon-mediated cell death associated with loss of TDP-43. Collectively, our study describes a role for TDP-43 in preventing the accumulation of endogenous immunostimulatory dsRNAs and uncovers an intricate relationship between the control of cellular gene expression and IFN-mediated cell death. Dunker et al. report that TDP-43 is involved in the regulation of immunostimulatory double-stranded RNA (dsRNA) homeostasis. TDP-43 associates with select RNA polymerase III transcripts, and its loss results in their increased expression and detection by RIG-I. This study furthers our understanding of intrinsic mechanisms regulating immunostimulatory dsRNA accumulation.
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