MEF2A suppresses stress responses that trigger DDX41-dependent IFN production
Julian R. Smith,
Jack W. Dowling,
Matthew I. McFadden,
Andrew Karp,
Johannes Schwerk,
Joshua J. Woodward,
Ram Savan,
Adriana Forero
Affiliations
Julian R. Smith
Department of Immunology, University of Washington, Seattle, WA 98109, USA
Jack W. Dowling
Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
Matthew I. McFadden
Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA
Andrew Karp
Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Discovery PREP, The Ohio State University, Columbus, OH 43210, USA
Johannes Schwerk
Department of Immunology, University of Washington, Seattle, WA 98109, USA
Joshua J. Woodward
Department of Microbiology, University of Washington, Seattle, WA 98109, USA
Ram Savan
Department of Immunology, University of Washington, Seattle, WA 98109, USA
Adriana Forero
Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Cancer Biology Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Infectious Diseases Institute, The Ohio State University, Columbus, OH 43210, USA; Corresponding author
Summary: Cellular stress in the form of disrupted transcription, loss of organelle integrity, or damage to nucleic acids can elicit inflammatory responses by activating signaling cascades canonically tasked with controlling pathogen infections. These stressors must be kept in check to prevent unscheduled activation of interferon, which contributes to autoinflammation. This study examines the role of the transcription factor myocyte enhancing factor 2A (MEF2A) in setting the threshold of transcriptional stress responses to prevent R-loop accumulation. Increases in R-loops lead to the induction of interferon and inflammatory responses in a DEAD-box helicase 41 (DDX41)-, cyclic GMP-AMP synthase (cGAS)-, and stimulator of interferon genes (STING)-dependent manner. The loss of MEF2A results in the activation of ATM and RAD3-related (ATR) kinase, which is also necessary for the activation of STING. This study identifies the role of MEF2A in sustaining transcriptional homeostasis and highlights the role of ATR in positively regulating R-loop-associated inflammatory responses.
