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NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22
Marianne R. Spalinger,1 Stephanie Kasper,1 Claudia Gottier,1 Silvia Lang,1 Kirstin Atrott,1 Stephan R. Vavricka,1,2 Sylvie Scharl,1 Tina Raselli,1 Isabelle Frey-Wagner,1 Petrus M. Gutte,3 Markus G. Grütter,3 Hans-Dietmar Beer,4 Emmanuel Contassot,4 Andrew C. Chan,5 Xuezhi Dai,6 David J. Rawlings,6 Florian Mair,7 Burkhard Becher,7 Werner Falk,8 Michael Fried,1,2 Gerhard Rogler,1,2 and Michael Scharl1,2
1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2Zurich Center for Integrative Human Physiology and
3Institute of Biochemistry, University of Zurich, Zurich, Switzerland.
4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
5Department of Immunology, Genentech, San Francisco, California, USA.
6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA.
7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
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First published November 1, 2016 - More info
J Clin Invest. 2016;126(11):4388–4388. https://doi.org/10.1172/JCI90897.
Copyright © 2016, American Society for Clinical Investigation
Related article:
Abstract
Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.
Authors
Marianne R. Spalinger, Stephanie Kasper, Claudia Gottier, Silvia Lang, Kirstin Atrott, Stephan R. Vavricka, Sylvie Scharl, Petrus M. Gutte, Markus G. Grütter, Hans-Dietmar Beer, Emmanuel Contassot, Andrew C. Chan, Xuezhi Dai, David J. Rawlings, Florian Mair, Burkhard Becher, Werner Falk, Michael Fried, Gerhard Rogler, Michael Scharl
1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. 2Zurich Center for Integrative Human Physiology and 3Institute of Biochemistry, University of Zurich, Zurich, Switzerland. 4Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland. 5Department of Immunology, Genentech, San Francisco, California, USA. 6Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA. 7Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. 8Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Original citation: J Clin Invest. 2016;126(5):1783–1800. doi:10.1172/JCI83669.
Citation for this corrigendum: J Clin Invest. 2016;126(11):4388. doi:10.1172/JCI90897.
Tina Raselli and Isabelle Frey-Wagner were inadvertently omitted from the author list. The correct author and affiliations list is above. The updated author contributions section is below.
MRS performed experiments, analyzed the data, and wrote the first draft of the manuscript. SK, CG, TR, IFW, SL, KA, and WF performed experiments and were involved in data analysis. PMG and MGG were involved in vector design and subcloning. DJR and XD generated PTPN22-619W mice. HDB and EC performed experiments in keratinocytes and were involved in data analysis and interpretation. FM and BB performed experiments. ACC corrected and approved the manuscript. SS, SRV, MF, GR, and MS were involved in acquisition of patient samples. MS and GR conceived, designed, and supervised the study. All authors wrote, corrected, and approved the manuscript.
The authors regret the errors.
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)