Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232-2363, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232-2363, USA; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-2363, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-2363, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN 37232-2363, USA; Vanderbilt Center for Immunobiology, Nashville, TN 37232-2363, USA.
Cell Rep. 2021 Apr 13;35(2):108976. doi: 10.1016/j.celrep.2021.108976.
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.
RIG-I 样受体（RLRs）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 广泛表达，但被细胞 RNA 结合蛋白（RBPs）破坏或隔离。TDP-43 是一种与多种神经退行性疾病相关的 RBP，对细胞活力至关重要。在这里，我们证明 TDP-43 调节免疫刺激性 dsRNA 的积累。免疫刺激性 RNA 被鉴定为 RNA 聚合酶 III 转录物，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）反应，从而促进坏死性凋亡。RLR 通路的遗传失活可挽救与 TDP-43 缺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和 IFN 介导的细胞死亡之间的复杂关系。
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