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

Area of Science:

• Molecular Biology
• Immunology
• Neuroscience

Background:

• RIG-I-like receptors (RLRs) detect double-stranded RNA (dsRNA) to distinguish self from non-self.
• Cellular RNA binding proteins (RBPs) like TDP-43 are crucial for managing endogenous dsRNA.
• TDP-43 dysfunction is linked to neurological disorders and cell viability.

Purpose of the Study:

• To investigate the role of TDP-43 in regulating immunostimulatory dsRNA.
• To identify the specific types of dsRNA regulated by TDP-43.
• To elucidate the downstream consequences of TDP-43-mediated dsRNA control on cellular immunity.

Main Methods:

• Characterization of dsRNA accumulation in TDP-43-deficient cells.
• Identification of RNA polymerase III transcripts (7SL, Alu retrotransposons) as immunostimulatory agents.
• Assessment of RIG-I-dependent interferon (IFN) response and necroptosis.
• Genetic analysis of RLR-pathway involvement in TDP-43 loss-associated cell death.

Main Results:

• TDP-43's RNA-binding activity is essential for preventing immune stimulation by endogenous dsRNA.
• Accumulation of immunostimulatory dsRNA, specifically RNA polymerase III transcripts, occurs upon TDP-43 loss.
• This dsRNA triggers a RIG-I-dependent IFN response, leading to necroptosis.
• Inactivating the RLR pathway rescues cells from interferon-mediated death following TDP-43 loss.

Conclusions:

• TDP-43 plays a critical role in suppressing endogenous immunostimulatory dsRNAs.
• A novel mechanism links cellular gene expression control by TDP-43 to interferon-mediated cell death.
• This discovery reveals an intricate relationship between RNA binding proteins, innate immunity, and neurological disease pathogenesis.