T helper 17 (Th17) cells are effector cells that mediate inflammatory responses to bacterial and fungal pathogens. While the cytokine signaling inputs required to generate Th17s are established, less is known about intracellular pathways that drive Th17 differentiation. Our previously published phosphoproteomic screen identifies that PIKFYVE, a lipid kinase that generates the phosphatidylinositol PtdIns(3,5)P2, is activated during Th17 differentiation. Herein, we discovered that PIKFYVE regulates kinase and transcription factor networks to promote Th17 differentiation. As a specific example, PtdIns(3,5)P2 directly stimulates mTORC1 kinase activity to promote cell division and differentiation pathways. Furthermore, PIKFYVE promotes STAT3 phosphorylation, which is required for Th17 differentiation. Chemical inhibition or CD4-specific deletion of PIKFYVE reduces Th17 differentiation and autoimmune pathology in the experimental autoimmune encephalomyelitis murine model of multiple sclerosis. Our findings identify molecular mechanisms by which PIKFYVE promotes Th17 differentiation and suggest that PIKFYVE is a potential therapeutic target in Th17-driven autoimmune diseases.
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December 31 2024
The phospholipid kinase PIKFYVE is essential for Th17 differentiation
Douglas S. Prado
,
Douglas S. Prado
(Conceptualization, Formal analysis, Investigation, Writing - original draft)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
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Richard T. Cattley
,
Richard T. Cattley
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Writing - review & editing)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
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Andreza B. Sonego
,
Andreza B. Sonego
(Formal analysis)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
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Parth Sutariya
,
Parth Sutariya
(Investigation)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
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Shuxian Wu
,
Shuxian Wu
(Resources)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
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Mijoon Lee
,
Mijoon Lee
(Methodology, Writing - review & editing)
3Department of Chemistry and Biochemistry,
University of Notre Dame
, Notre Dame, IN, USA
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William C. Boggess
,
William C. Boggess
(Methodology, Writing - review & editing)
3Department of Chemistry and Biochemistry,
University of Notre Dame
, Notre Dame, IN, USA
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Mark J. Shlomchik
,
Mark J. Shlomchik
(Conceptualization, Methodology, Resources, Writing - review & editing)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
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William F. Hawse
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
Correspondence to William F. Hawse: [email protected]
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Douglas S. Prado
Conceptualization, Formal analysis, Investigation, Writing - original draft
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
Richard T. Cattley
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Writing - review & editing
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
Andreza B. Sonego
Formal analysis
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
Parth Sutariya
Investigation
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
Shuxian Wu
Resources
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
Mijoon Lee
Methodology, Writing - review & editing
3Department of Chemistry and Biochemistry,
University of Notre Dame
, Notre Dame, IN, USA
William C. Boggess
Methodology, Writing - review & editing
3Department of Chemistry and Biochemistry,
University of Notre Dame
, Notre Dame, IN, USA
Mark J. Shlomchik
Conceptualization, Methodology, Resources, Writing - review & editing
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
William F. Hawse
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Immunology,
University of Pittsburgh
, Pittsburgh, PA, USA
2
Center for Systems Immunology, University of Pittsburgh
, Pittsburgh, PA, USA
Correspondence to William F. Hawse: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
April 22 2024
Revision Received:
June 13 2024
Accepted:
December 02 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funder(s):
University of Pittsburgh
Funder(s):
National Institutes of Health
- Award Id(s): 1R01AI175111
© 2024 Prado et al.
2024
Prado et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (2): e20240625.
Article history
Received:
April 22 2024
Revision Received:
June 13 2024
Accepted:
December 02 2024
Citation
Douglas S. Prado, Richard T. Cattley, Andreza B. Sonego, Parth Sutariya, Shuxian Wu, Mijoon Lee, William C. Boggess, Mark J. Shlomchik, William F. Hawse; The phospholipid kinase PIKFYVE is essential for Th17 differentiation. J Exp Med 3 February 2025; 222 (2): e20240625. doi: https://doi.org/10.1084/jem.20240625
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