Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung
Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase (JAK) 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 unkno...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00514/full |
| _version_ | 1818607938907930624 |
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| author | Jana Zimmer Michael Weitnauer Sébastien Boutin Sébastien Boutin Sébastien Boutin Günter Küblbeck Sabrina Thiele Patrick Walker Felix Lasitschka Lars Lunding Lars Lunding Zane Orinska Zane Orinska Christina Vock Christina Vock Bernd Arnold Michael Wegmann Michael Wegmann Alexander Dalpke Alexander Dalpke Alexander Dalpke |
| author_facet | Jana Zimmer Michael Weitnauer Sébastien Boutin Sébastien Boutin Sébastien Boutin Günter Küblbeck Sabrina Thiele Patrick Walker Felix Lasitschka Lars Lunding Lars Lunding Zane Orinska Zane Orinska Christina Vock Christina Vock Bernd Arnold Michael Wegmann Michael Wegmann Alexander Dalpke Alexander Dalpke Alexander Dalpke |
| author_sort | Jana Zimmer |
| collection | DOAJ |
| description | Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase (JAK) 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 three 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 NFB 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 (TER) 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. |
| first_indexed | 2024-12-16T14:34:42Z |
| format | Article |
| id | doaj.art-c89f0a8f36564b6990ecfe7267927e16 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T14:34:42Z |
| publishDate | 2016-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c89f0a8f36564b6990ecfe7267927e162022-12-21T22:28:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-11-01710.3389/fimmu.2016.00514229328Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lungJana Zimmer0Michael Weitnauer1Sébastien Boutin2Sébastien Boutin3Sébastien Boutin4Günter Küblbeck5Sabrina Thiele6Patrick Walker7Felix Lasitschka8Lars Lunding9Lars Lunding10Zane Orinska11Zane Orinska12Christina Vock13Christina Vock14Bernd Arnold15Michael Wegmann16Michael Wegmann17Alexander Dalpke18Alexander Dalpke19Alexander Dalpke20University Hospital HeidelbergUniversity Hospital HeidelbergUniversity Hospital HeidelbergTranslational Lung Research Center Heidelberg (TLRC)German Center for Lung Research (DZL)German Cancer Research Center (DKFZ)University Hospital HeidelbergUniversity Hospital HeidelbergUniversity Hospital HeidelbergResearch Center BorstelAirway Research Center NorthResearch Center BorstelAirway Research Center NorthResearch Center BorstelAirway Research Center NorthGerman Cancer Research Center (DKFZ)Research Center BorstelAirway Research Center NorthUniversity Hospital HeidelbergTranslational Lung Research Center Heidelberg (TLRC)German Center for Lung Research (DZL)Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase (JAK) 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 three 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 NFB 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 (TER) 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.http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00514/fullInflammationLungSignal TransductionrodentTransgenic micecytokine signaling |
| spellingShingle | Jana Zimmer Michael Weitnauer Sébastien Boutin Sébastien Boutin Sébastien Boutin Günter Küblbeck Sabrina Thiele Patrick Walker Felix Lasitschka Lars Lunding Lars Lunding Zane Orinska Zane Orinska Christina Vock Christina Vock Bernd Arnold Michael Wegmann Michael Wegmann Alexander Dalpke Alexander Dalpke Alexander Dalpke Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung Frontiers in Immunology Inflammation Lung Signal Transduction rodent Transgenic mice cytokine signaling |
| title | Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung |
| title_full | Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung |
| title_fullStr | Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung |
| title_full_unstemmed | Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung |
| title_short | Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung |
| title_sort | nuclear localization of suppressor of cytokine signaling socs 1 regulates local immunity in the lung |
| topic | Inflammation Lung Signal Transduction rodent Transgenic mice cytokine signaling |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00514/full |
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