Respiratory viruses activate autophagy via the IFN-STAT1/STAT5B-SOCS1 axis

作者：Victoria Hunszinger, Helen Dürr, Zoé Engels, Helene Hoenigsperger, Lennart Koepke, Susanne Klute, Jana-Romana Fischer, Birgit Ott, Alexander Graf, Stefan Krebs, Helmut Blum, Maximilian Hirschenberger, Frank Kirchhoff, Konstantin M. J. Sparrer · 发表于：PLoS Pathogens · 年份：2026 · DOI：10.1371/journal.ppat.1014414 · 研究领域：Autophagy in Disease and Therapy、interferon and immune responses、Respiratory viral infections research

Abstract Autophagy is an ancient catabolic process that has emerged as part of the innate immunity. Upon infection, autophagy is activated but key factors responsible remained unclear. Here, we show that interferon (IFN) released during viral infections subsequently activates autophagy via STAT1/5B-mediated upregulation of SOCS1. Our data shows that scavenging of IFNs diminishes autophagy induced by several respiratory viruses. All types of IFN (I, II and III) mediated robust autophagic flux activation in both cell lines and primary human lung fibroblasts in a JAK1-3 dependent manner. Depletion or pharmacological inhibition of individual STAT transcription factors demonstrated that both STAT1 and STAT5B are required for IFN-induced autophagy. Upon IFN stimulation STAT1 and STAT5B associate and translocate to the nucleus. Transcriptome analyses revealed that inhibition of STAT5 only reduces expression of a subset of IFN-stimulated genes, whereas most known anti-viral IFN-stimulated genes remain induced to high levels. Among the STAT5 dependent genes was Suppressor of Cytokine Signaling 1 (SOCS1). Overexpression of SOCS1 stimulated autophagy, whereas its depletion impaired IFN-induced autophagy. Successful viruses like measles virus (MeV) or respiratory syncytial viruses (RSV) evolved strategies to exploit autophagy to promote their own replication. Uncoupling IFN-mediated ISG defenses from autophagy induction using by STAT5 inhibition reduced virus-induced autophagy, and inhib...