Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung

Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase and signal transducer and activator of transcription (STAT) signaling. SOCS1 also contains a nuclear localization sequence (NLS), yet, the in vivo importance of nuclear translocation is unknown. W...

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Main Authors:	Zimmer, Jana, Weitnauer, Michael, Boutin, Sébastien, Küblbeck, Günter, Thiele, Sabrina, Walker, Patrick, Lasitschka, Felix, Lunding, Lars, Orinska, Zane, Vock, Christina, Arnold, Bernd, Wegmann, Michael, Dalpke, Alexander
Format:	Online
Language:	English
Published:	Frontiers Media S.A. 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114302/

id	pubmed-5114302
recordtype	oai_dc
spelling	pubmed-51143022016-12-02 Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung Zimmer, Jana Weitnauer, Michael Boutin, Sébastien Küblbeck, Günter Thiele, Sabrina Walker, Patrick Lasitschka, Felix Lunding, Lars Orinska, Zane Vock, Christina Arnold, Bernd Wegmann, Michael Dalpke, Alexander Immunology Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase and signal transducer and activator of transcription (STAT) signaling. SOCS1 also contains a nuclear localization sequence (NLS), yet, the in vivo importance of nuclear translocation is unknown. We generated transgenic mice containing mutated Socs1ΔNLS that fails to translocate in the cell nucleus (MGLtg mice). Whereas mice fully deficient for SOCS1 die within the first 3 weeks due to excessive interferon signaling and multiorgan inflammation, mice expressing only non-nuclear Socs1ΔNLS (Socs1−/−MGLtg mice) were rescued from early lethality. Canonical interferon gamma signaling was still functional in Socs1−/−MGLtg mice as shown by unaltered tyrosine phosphorylation of STAT1 and whole genome expression analysis. However, a subset of NFκB inducible genes was dysregulated. Socs1−/−MGLtg mice spontaneously developed low-grade inflammation in the lung and had elevated Th2-type cytokines. Upon ovalbumin sensitization and challenge, airway eosinophilia was increased in Socs1−/−MGLtg mice. Decreased transepithelial electrical resistance in trachea epithelial cells from Socs1−/−MGLtg mice suggests disrupted epithelial cell barrier. The results indicate that nuclear SOCS1 is a regulator of local immunity in the lung and unravel a so far unrecognized function for SOCS1 in the cell nucleus. Frontiers Media S.A. 2016-11-18 /pmc/articles/PMC5114302/ /pubmed/27917175 http://dx.doi.org/10.3389/fimmu.2016.00514 Text en Copyright © 2016 Zimmer, Weitnauer, Boutin, Küblbeck, Thiele, Walker, Lasitschka, Lunding, Orinska, Vock, Arnold, Wegmann and Dalpke. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Zimmer, Jana Weitnauer, Michael Boutin, Sébastien Küblbeck, Günter Thiele, Sabrina Walker, Patrick Lasitschka, Felix Lunding, Lars Orinska, Zane Vock, Christina Arnold, Bernd Wegmann, Michael Dalpke, Alexander
spellingShingle	Zimmer, Jana Weitnauer, Michael Boutin, Sébastien Küblbeck, Günter Thiele, Sabrina Walker, Patrick Lasitschka, Felix Lunding, Lars Orinska, Zane Vock, Christina Arnold, Bernd Wegmann, Michael Dalpke, Alexander Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung
author_facet	Zimmer, Jana Weitnauer, Michael Boutin, Sébastien Küblbeck, Günter Thiele, Sabrina Walker, Patrick Lasitschka, Felix Lunding, Lars Orinska, Zane Vock, Christina Arnold, Bernd Wegmann, Michael Dalpke, Alexander
author_sort	Zimmer, Jana
title	Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung
title_short	Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung
title_full	Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung
title_fullStr	Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung
title_full_unstemmed	Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung
title_sort	nuclear localization of suppressor of cytokine signaling-1 regulates local immunity in the lung
description	Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase and signal transducer and activator of transcription (STAT) signaling. SOCS1 also contains a nuclear localization sequence (NLS), yet, the in vivo importance of nuclear translocation is unknown. We generated transgenic mice containing mutated Socs1ΔNLS that fails to translocate in the cell nucleus (MGLtg mice). Whereas mice fully deficient for SOCS1 die within the first 3 weeks due to excessive interferon signaling and multiorgan inflammation, mice expressing only non-nuclear Socs1ΔNLS (Socs1−/−MGLtg mice) were rescued from early lethality. Canonical interferon gamma signaling was still functional in Socs1−/−MGLtg mice as shown by unaltered tyrosine phosphorylation of STAT1 and whole genome expression analysis. However, a subset of NFκB inducible genes was dysregulated. Socs1−/−MGLtg mice spontaneously developed low-grade inflammation in the lung and had elevated Th2-type cytokines. Upon ovalbumin sensitization and challenge, airway eosinophilia was increased in Socs1−/−MGLtg mice. Decreased transepithelial electrical resistance in trachea epithelial cells from Socs1−/−MGLtg mice suggests disrupted epithelial cell barrier. The results indicate that nuclear SOCS1 is a regulator of local immunity in the lung and unravel a so far unrecognized function for SOCS1 in the cell nucleus.
publisher	Frontiers Media S.A.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114302/
_version_	1613731938576629760

Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung

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