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

RIG-I-like receptors (RLRs) are involved in the discrimination of self vs non-self via the recognition of dsRNA. Emerging evidence suggests that immunostimulatory dsRNAs are ubiquitously expressed yet they 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 was 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 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. Profiling the gene expression after TDP-43 knockdown in SH-SY5Y cells.