Interferon-stimulated gene MCL1 inhibits foot-and-mouth disease virus replication by modulating mitochondrial dynamics and autophagy

• Published in: Journal of virology Vol. 99; no. 7; p. e0058125
• Main Authors: Mogulothu, Aishwarya, Hickman, Danielle, Attreed, Sarah, Azzinaro, Paul, Rodriguez-Calzada, Monica, Dittmann, Meike, de los Santos, Teresa, Szczepanek, Steven, Medina, Gisselle N.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 22.07.2025
• Subjects: Animals; Autophagy; Cell Line; Foot-and-Mouth Disease - genetics; Foot-and-Mouth Disease - virology; Foot-and-Mouth Disease Virus - physiology; Interferons - metabolism; Mitochondria - metabolism; Mitochondrial Dynamics - genetics; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Swine; Virology; Virus Replication; Virus-Cell Interactions; foot-and-mouth disease virus; autophagy; interferons; interferon-stimulated genes; antiviral agents; mitochondrial metabolism
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/jvi.00581-25

In this study, we have successfully used a high-throughput ISG screening approach to measure the inhibition of FMDV replication using an RNA replicon system for the first time. This screen led to the identification of the potent antiviral effects of a relatively lesser-known ISG called MCL1. Our findings reveal that MCL1 exerts its antiviral functions through the regulation of mitochondrial dynamics and autophagy. Although mitochondrial dynamics are involved in apoptosis, metabolism, redox homeostasis, stress responses, and antiviral signaling, this pathway has not been thoroughly explored in the context of FMDV infection. Further investigation into mitochondrial dynamics may facilitate the development of improved biotherapeutics for FMDV. Additionally, our studies highlight the significance of autophagy, a pathway that is needed by FMDV for replication. Ultimately, a deep understanding of all mechanisms exploited by FMDV may allow for the rational design of novel therapeutics and vaccines to control FMD.