University of Sussex
Browse
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

Download (2.58 MB)
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 Cooke
Emerging 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 ONE

ISSN

1932-6203

Publisher

Public Library of Science

Issue

6

Volume

10

Article number

e0131071

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Sussex Drug Discovery Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-08-15

First Open Access (FOA) Date

2018-08-15

First Compliant Deposit (FCD) Date

2018-08-15

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC