Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors

Nat Commun. 2017 Jun 9:8:15732. doi: 10.1038/ncomms15732.

Abstract

Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR-induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, where IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1-F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Calcium / metabolism
  • Calcium Signaling*
  • Catalytic Domain
  • Cell Differentiation
  • Cell Proliferation
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Inositol / metabolism
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Jurkat Cells
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Phospholipase C gamma / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Receptors, Antigen, T-Cell / metabolism
  • Recombination, Genetic
  • Signal Transduction
  • Thymocytes / cytology
  • Thymocytes / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • ITPR1 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Receptors, Antigen, T-Cell
  • TESPA1 protein, human
  • Tespa1 protein, mouse
  • Inositol
  • Inositol 1,4,5-Trisphosphate
  • Phospholipase C gamma
  • Calcium