The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P 2 replenishment in response to TCR signaling during T cell development and survival.

Autor: Lu W; Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA., Helou YA; Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Clade Therapeutics, Cambridge, MA, USA., Shrinivas K; NSF-Simons Center for Mathematical & Statistical Analysis of Biology, Harvard University, Cambridge, MA, USA., Liou J; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Au-Yeung BB; Division of Immunology, Lowance Center for Human Immunology, Department of Medicine, Emory University, Atlanta, GA, USA., Weiss A; Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. Arthur.Weiss@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2023 Jan; Vol. 24 (1), pp. 136-147. Date of Electronic Publication: 2022 Dec 29.
DOI: 10.1038/s41590-022-01372-2
Abstrakt: Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) by phospholipase C-γ (PLCγ1) represents a critical step in T cell antigen receptor (TCR) signaling and subsequent thymocyte and T cell responses. PIP 2 replenishment following its depletion in the plasma membrane (PM) is dependent on delivery of its precursor phosphatidylinositol (PI) from the endoplasmic reticulum (ER) to the PM. We show that a PI transfer protein (PITP), Nir3 (Pitpnm2), promotes PIP 2 replenishment following TCR stimulation and is important for T cell development. In Nir3 -/- T lineage cells, the PIP 2 replenishment following TCR stimulation is slower. Nir3 deficiency attenuates calcium mobilization in double-positive (DP) thymocytes in response to weak TCR stimulation. This impaired TCR signaling leads to attenuated thymocyte development at TCRβ selection and positive selection as well as diminished mature T cell fitness in Nir3 -/- mice. This study highlights the importance of PIP 2 replenishment mediated by PITPs at ER-PM junctions during TCR signaling.
(© 2022. The Author(s).)
Databáze: MEDLINE
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