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

doi:10.1016/j.celrep.2023.112805

MEF2A suppresses stress responses that trigger DDX41-dependent IFN production

Cell Rep. 2023 Aug 29;42(8):112805. doi: 10.1016/j.celrep.2023.112805. Epub 2023 Jul 18.

Authors

Julian R Smith¹, Jack W Dowling², Matthew I McFadden³, Andrew Karp⁴, Johannes Schwerk¹, Joshua J Woodward⁵, Ram Savan¹, Adriana Forero⁶

Affiliations

¹ Department of Immunology, University of Washington, Seattle, WA 98109, USA.
² Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
³ 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.
⁴ 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.
⁵ Department of Microbiology, University of Washington, Seattle, WA 98109, USA.
⁶ 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. Electronic address: [email protected].

Abstract

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.

Keywords: CP: Immunology; CP: Molecular biology; DDX41; DNA damage; MEF2A; cytokine regulation; innate immunity; interferons; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Immunity, Innate
Interferons
Nucleotidyltransferases* / metabolism
RNA Helicases
Signal Transduction*

Substances

Nucleotidyltransferases
RNA Helicases
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding