STAT2 is a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways

Ho, Johnathan; Pelzel, Christin; Begitt, Andreas; Mee, Maureen; Elsheikha, Hany M.; Scott, David J.; Vinkemeier, Uwe

Abstract

STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-?, interleukin-6 (IL-6) and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-? binding. This, in turn, substantially attenuated cardinal IFN-? responses including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon independent activities of this protein.

Citation

Ho, J., Pelzel, C., Begitt, A., Mee, M., Elsheikha, H. M., Scott, D. J., & Vinkemeier, U. (2016). STAT2 is a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways. PLoS Biology, 14(10), 1-27. https://doi.org/10.1371/journal.pbio.2000117

• Journal Article Type: Article
• Acceptance Date: Sep 7, 2016
• Online Publication Date: Oct 25, 2016
• Publication Date: Oct 25, 2016
• Deposit Date: Oct 17, 2016
• Publicly Available Date: Oct 25, 2016
• Journal: PLoS Biology
• Print ISSN: 1544-9173
• Electronic ISSN: 1545-7885
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 10
• Article Number: e2000117
• Pages: 1-27
• DOI: https://doi.org/10.1371/journal.pbio.2000117
• Public URL: https://nottingham-repository.worktribe.com/output/821692
• Publisher URL: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000117