Selective decay of interferon mRNAs controls antiviral immunity and innate memory
Year: 2026
Type: article
Abstract: Homeostatic control of interferon (IFN) signaling is essential, as dysregulation leads to poor outcomes. While the stimuli-dependent induction of IFNs is well understood, less is known about how IFN mRNAs are maintained at low levels basally or rapidly returned to baseline post-stimulation. We find that selective post-transcriptional control of type I and type III IFN mRNAs by the RNA-binding specificity factor tristetraprolin (TTP) and mRNA decay machinery contributes to homeostatic control by negatively regulating IFN mRNAs at steady state and post-stimulation. Loss of this pathway leads to increased poly(A) tail length, stability, and translation. This increases expression of IFNs, potently blocking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro and in vivo. A human TTP variant associated with autoimmunity shows decreased TTP levels and increased IFN signaling, further demonstrating that regulation by this pathway impacts disease. Prolonged IFN signaling driven by transient loss of mRNA decay primes cells, inducing innate memory and providing long-term antiviral protection.
Source: Molecular Cell
Authors: Rachel M. Braun, Max B. Ferretti, Jae Seung Lee, Jesse Miller, Lauren Castellana, Jorge Acuña, Kanupriya Whig, Lenka Dohnalová, Hélène C. Descamps, Alex S. Huber, Hiromi Muramatsu, Peter Hewins, Yue Li, Smita Bhutda, Zienab Etwebi, Mark Dittmar, Thomasina Cook, David C. Schultz, Perry J. Blackshear, Kellie Ann Jurado, Christoph A. Thaiss, Norbert Pardi, Kristen W. Lynch, Sara Cherry
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: Mercatus Center, George Mason University, Burroughs Wellcome Fund, Bill and Melinda Gates Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Mark Foundation For Cancer Research, National Institutes of Health, Innovation Fund, Penn Center for Precision Medicine, University of Pennsylvania, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences
Awards: University of Pennsylvania - to test the ReFrame library in human lung cell line infected with SARS2, Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses., The role of pattern recognition and autophagy in innate anti-bunyaviral immunity, G3968479124, Training in Virology, Defining the functional interface between the ER and flaviviruses, G9000085644, G9000310761, Signal-Induced Regulation of Alternative RNA Processing
OpenAlex ID: W7203480558