journal.pone.0131071.PDF (2.58 MB)
Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease
journal contribution
posted on 2023-06-09, 14:33 authored by Andrew T Miller, Carol Dahlberg, Mark L Sandberg, Ben G Wen, Daniel R Beisner, John A H Hoerter, Albert Parker, Christian Schmedt, Monique Stinson, Jacqueline Avis, Cynthia Cienfuegos, Mark McPate, Pamela Tranter, Martin Gosling, Paul J Groot-Kormelink, Janet Dawson, Shifeng Pan, Shin-Shay Tian, H Martin Seidel, Michael P CookeEmerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease.
History
Publication status
- Published
File Version
- Published version
Journal
PLoS ONEISSN
1932-6203Publisher
Public Library of ScienceExternal DOI
Issue
6Volume
10Article number
e0131071Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Sussex Drug Discovery Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-15First Open Access (FOA) Date
2018-08-15First Compliant Deposit (FCD) Date
2018-08-15Usage metrics
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