SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ
The biologic effects of IFNγ are mediated by the transcription factor STAT1. The activity of STAT1 is inhibited by small ubiquitin-like modifier (SUMO) conjugation. This occurs both directly through decreasing STAT1 tyrosine phosphorylation and indirectly by facilitating STAT1 dephosphorylation cons...
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American Society for Hematology
2011
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| Online Access: | https://eprints.nottingham.ac.uk/2930/ |
| _version_ | 1848790911694143488 |
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| author | Begitt, Andreas Droescher, Mathias Knobeloch, Klaus-Peter Vinkemeier, Uwe |
| author_facet | Begitt, Andreas Droescher, Mathias Knobeloch, Klaus-Peter Vinkemeier, Uwe |
| author_sort | Begitt, Andreas |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | The biologic effects of IFNγ are mediated by the transcription factor STAT1. The activity of STAT1 is inhibited by small ubiquitin-like modifier (SUMO) conjugation. This occurs both directly through decreasing STAT1 tyrosine phosphorylation and indirectly by facilitating STAT1 dephosphorylation consequential to increased STAT1 solubility because of suppressed paracrystal assembly. However, the physiologic implications of SUMO conjugation have remained unclear. Here, we used fibroblasts and bone marrow–derived macrophages (BMMs) from knockin mice expressing SUMO-free STAT1 to explore the consequences of STAT1 sumoylation for IFNγ signaling. Our experiments demonstrated buffer property of paracrystals for activated STAT1, such that SUMO-mediated paracrystal dispersal profoundly reduced phosphorylation of STAT1, which affected both the activating tyrosine 701 and the transcription-enhancing serine 727. Accordingly, the curtailed STAT1 activity in the nucleus caused by SUMO conjugation resulted in diminished transcription of IFNγ-responsive genes; and increased the IFNγ concentration more than 100-fold required to trigger lipopolysaccharide-induced cytotoxicity in bone marrow–derived macrophages. These experiments identify SUMO conjugation of STAT1 as a mechanism to permanently attenuate the IFNγ sensitivity of cells, which prevents hyperresponsiveness to this cytokine and its potentially self-destructive consequences. This sets the mode of SUMO-mediated inhibition apart from the other negative STAT regulators known to date. |
| first_indexed | 2025-11-14T18:20:08Z |
| format | Article |
| id | nottingham-2930 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T18:20:08Z |
| publishDate | 2011 |
| publisher | American Society for Hematology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-29302020-05-04T16:30:48Z https://eprints.nottingham.ac.uk/2930/ SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ Begitt, Andreas Droescher, Mathias Knobeloch, Klaus-Peter Vinkemeier, Uwe The biologic effects of IFNγ are mediated by the transcription factor STAT1. The activity of STAT1 is inhibited by small ubiquitin-like modifier (SUMO) conjugation. This occurs both directly through decreasing STAT1 tyrosine phosphorylation and indirectly by facilitating STAT1 dephosphorylation consequential to increased STAT1 solubility because of suppressed paracrystal assembly. However, the physiologic implications of SUMO conjugation have remained unclear. Here, we used fibroblasts and bone marrow–derived macrophages (BMMs) from knockin mice expressing SUMO-free STAT1 to explore the consequences of STAT1 sumoylation for IFNγ signaling. Our experiments demonstrated buffer property of paracrystals for activated STAT1, such that SUMO-mediated paracrystal dispersal profoundly reduced phosphorylation of STAT1, which affected both the activating tyrosine 701 and the transcription-enhancing serine 727. Accordingly, the curtailed STAT1 activity in the nucleus caused by SUMO conjugation resulted in diminished transcription of IFNγ-responsive genes; and increased the IFNγ concentration more than 100-fold required to trigger lipopolysaccharide-induced cytotoxicity in bone marrow–derived macrophages. These experiments identify SUMO conjugation of STAT1 as a mechanism to permanently attenuate the IFNγ sensitivity of cells, which prevents hyperresponsiveness to this cytokine and its potentially self-destructive consequences. This sets the mode of SUMO-mediated inhibition apart from the other negative STAT regulators known to date. American Society for Hematology 2011-07-28 Article PeerReviewed Begitt, Andreas, Droescher, Mathias, Knobeloch, Klaus-Peter and Vinkemeier, Uwe (2011) SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ. Blood, 118 (4). pp. 1002-1007. ISSN 0006-4971 http://bloodjournal.hematologylibrary.org/content/118/4/1002.abstract?sid=acbbbdcc-e607-40b9-891a-d4c267f30a0f doi:10.1182/blood-2011-04-347930 doi:10.1182/blood-2011-04-347930 |
| spellingShingle | Begitt, Andreas Droescher, Mathias Knobeloch, Klaus-Peter Vinkemeier, Uwe SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ |
| title | SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ |
| title_full | SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ |
| title_fullStr | SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ |
| title_full_unstemmed | SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ |
| title_short | SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ |
| title_sort | sumo conjugation of stat1 protects cells from hyperresponsiveness to ifnγ |
| url | https://eprints.nottingham.ac.uk/2930/ https://eprints.nottingham.ac.uk/2930/ https://eprints.nottingham.ac.uk/2930/ |