TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response

• Main Authors: William Dunker, Xiang Ye, Yang Zhao, Lanxi Liu, Antiana Richardson, John Karijolich
• Format: Article
• Language: English
• Published: Elsevier 2021-04-01
• Series: Cell Reports
• Subjects: TDP-43; double-stranded RNA; RIG-I-like receptors; RNA binding protein; necroptosis; gene expression
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721002904

Summary: 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.