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Upon infection, autophagy is activated but the key factors responsible remained unclear. Here, we show that interferon (IFN) released during viral infections subsequently activates autophagy via STAT1\/5B-mediated upregulation of Suppressor of Cytokine Signaling 1 (SOCS1). Our data show 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\u20133 dependent manner. Depletion or pharmacological inhibition of individual signal transducer and activator of transcription (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 most known anti-viral IFN-stimulated genes (ISGs) remain induced to high levels upon inhibition of STAT5 expect for a small subset of ISGs, among them SOCS1. Overexpression of SOCS1 stimulated autophagy, whereas its depletion impaired IFN-induced autophagy. Successful viruses like measles virus (MeV) or respiratory syncytial virus (RSV) evolved strategies to exploit autophagy to promote their own replication. Uncoupling IFN-mediated ISG defenses from autophagy induction by STAT5 inhibition reduced virus-induced autophagy, and inhibited efficient replication of autophagy-dependent MeV and RSV. Overexpression of SOCS1 upon STAT5 inhibition largely rescued both infection-induced autophagy and viral replication. Taken together, our data show that IFN promotes autophagy via STAT1\/STAT5B-SOCS1 in viral infections and reveal that targeting of this axis allows inhibition of autophagy-dependent viruses without compromising innate immune defenses.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014414","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:47:08Z","timestamp":1784137628000},"page":"e1014414","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Respiratory viruses activate autophagy via the IFN-STAT1\/STAT5B-SOCS1 axis"],"prefix":"10.1371","volume":"22","author":[{"given":"Victoria","family":"Hunszinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Klute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00e9","family":"Engels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Hoenigsperger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennart","family":"Koepke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"D\u00fcrr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana-Romana","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Graf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Krebs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Blum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Kirchhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8766-1271","authenticated-orcid":true,"given":"Maximilian","family":"Hirschenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8682-1779","authenticated-orcid":true,"given":"Konstantin M. 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