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Interferons promote autophagy via the STAT1/STAT5B-SOCS1 axis

ABSTRACT: Concerted activation of the interferon (IFN) system and autophagy upon viral infection is paramount for efficient immune defences. Here, we show that IFN activates autophagy via STAT1/5B heterodimer-mediated upregulation of SOCS1 and contributes to virus-induced autophagy. Our data demonstrate that autophagic flux activation by type I and II IFNs peaks at 24 h post treatment, whereas type III IFNs induce autophagy with slower kinetics. Mechanistically, IFN-mediated autophagy induction is dependent on JAK1-3 and both STAT1 as well as STAT5B. We show that STAT1 and STAT5B form heterodimers and co-localize following IFN treatment. Transcriptome analyses revealed that SOCS1 is induced in a STAT5B-dependent manner, and depletion of SOCS1 prevented IFN-induced autophagy. Finally, pharmacological inhibition of STAT5B or scavenging of IFN diminishes autophagosome levels upon infection with Sendai, respiratory syncytial, measles and influenza A viruses. Taken together, our data indicate that the IFN system and autophagy are connected via the STAT1/STAT5B-SOCS1 axis and that this axis is required for concerted activation of both systems during viral infections. Targeting of this signalling axis may allow to boost autophagy against viral infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302359 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Compared to primary human monocytes in whole blood cultures, few B cells activated STAT1 in response to stimulation of 2000 IU/ml IFN-beta for 45 minutes. Because activation of STAT1 leads to apoptosis induction, we tested the hypothesis that less pro-apoptotic genes are induced in B cells as compared to monocytes. Manuscript titled: Major differences in the responses of primary human leukocyte subsets to IFN-beta. Abstract: Treatment of cell lines with type I IFNs activates the formation of ISGF3 (STAT1/STAT2/ IRF9), which induces the expression of many genes. To study this response in primary cells, we treated fresh human blood with IFN-beta and used flow cytometry to analyze phosphorylated STATs1, 3 and 5 in CD4+ and CD8+ T cells, B cells, and monocytes. The activation of STAT1 was remarkably different among these leukocyte subsets. In contrast to monocytes, CD4+ and CD8+ T cells, few B cells activated STAT1 in response to IFN-beta, a finding that could not be explained by decreased levels of IFNAR2 or STAT1 or enhanced levels of SOCS1 or relevant protein tyrosine phosphatases in B cells. Micro-array and real-time PCR analyses revealed the induction of STAT1-dependent pro-apoptotic mRNAs in monocytes but not in B cells. These data show that ISGF3 or STAT1 homodimers are not the main activators of gene expression in primary B cells of healthy humans. Notably, in B cells and especially in CD4+ T cells, IFN-beta activated STAT5 in addition to STAT3, with biological effects often opposite from those driven by activated STAT1. These data help to explain why IFN-beta increases the survival of primary human B cells and CD4+ T cells, but enhances the apoptosis of monocytes, and also to understand how leukocyte subsets are differentially affected by endogenous type I IFNs during viral or bacterial infections, and by type I IFN treatment of patients with multiple sclerosis, hepatitis or cancer. Undiluted whole blood of 2 healthy individuals (HI) was used, and either stimulated with IFN-beta or left untreated (control) for 3 hrs. After 3 hrs, both B cells and monocytes were isolated from whole blood of the first healthy individual, and only B cells were isolated from whole blood of the second healthy individual.

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Interferons promote autophagy via the STAT1/STAT5B-SOCS1 axis

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