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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

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


Authors

Johnathan Ho

Christin Pelzel

Maureen Mee

DAVID SCOTT DAVID.SCOTT@NOTTINGHAM.AC.UK
Associate Professor & Reader in Physical Biochemistry

UWE VINKEMEIER uwe.vinkemeier@nottingham.ac.uk
Action Medical Research Professor of Cell Biology



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-γ, 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-α binding. This, in turn, substantially attenuated cardinal IFN-γ 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
Contract Date Oct 17, 2016

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