Johnathan Ho
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
Authors
Christin Pelzel
ANDREAS BEGITT andreas.begitt@nottingham.ac.uk
Research Fellow
Maureen Mee
Professor HANY ELSHEIKHA hany.elsheikha@nottingham.ac.uk
Professor of Interdisciplinary Parasitology
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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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
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