Autoimmune Disorders Associated with Gain of Function of the Intracellular Sensor MDA5

TLDR

MDA5 is a viral dsRNA sensor that triggers interferon responses and has been linked to autoimmunity, though how it contributes remains unclear. The authors generated an ENU‑induced MDA5 mutant mouse that spontaneously develops lupus‑like disease in the absence of viral infection. The mutant activates MAVS‑dependent signaling without ligand, is defective for ligand‑induced responses, and its loss of IFNAR signaling ameliorates disease, demonstrating that MDA5 dysregulation drives autoimmunity and revealing a conformational change underlying this effect.

Abstract

MDA5 is an essential intracellular sensor for several viruses, including picornaviruses, and elicits antiviral interferon (IFN) responses by recognizing viral dsRNAs. MDA5 has been implicated in autoimmunity. However, the mechanisms of how MDA5 contributes to autoimmunity remain unclear. Here we provide direct evidence that dysregulation of MDA5 caused autoimmune disorders. We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection. Inflammation was dependent on an adaptor molecule, MAVS indicating the importance of MDA5-signaling. In addition, intercrossing the mutant mice with type I IFN receptor-deficient mice ameliorated clinical manifestations. This MDA5 mutant could activate signaling in the absence of its ligand but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.