The Ciliary Machinery Is Repurposed for T Cell Immune Synapse Trafficking of LCK

Dev Cell. 2018 Oct 8;47(1):122-132.e4. doi: 10.1016/j.devcel.2018.08.012. Epub 2018 Sep 13.

Abstract

Upon engagement of the T cell receptor with an antigen-presenting cell, LCK initiates TCR signaling by phosphorylating its activation motifs. However, the mechanism of LCK activation specifically at the immune synapse is a major question. We show that phosphorylation of the LCK activating Y394, despite modestly increasing its catalytic rate, dramatically focuses LCK localization to the immune synapse. We describe a trafficking mechanism whereby UNC119A extracts membrane-bound LCK by sequestering the hydrophobic myristoyl group, followed by release at the target membrane under the control of the ciliary ARL3/ARL13B. The UNC119A N terminus acts as a "regulatory arm" by binding the LCK kinase domain, an interaction inhibited by LCK Y394 phosphorylation, thus together with the ARL3/ARL13B machinery ensuring immune synapse focusing of active LCK. We propose that the ciliary machinery has been repurposed by T cells to generate and maintain polarized segregation of signals such as activated LCK at the immune synapse.

Keywords: ARL13B; ARL3; GDI; LCK; Src kinases; UNC119; cilia; immunological synapse; protein trafficking; small GTPases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Antigen-Presenting Cells / immunology
  • Cilia / physiology*
  • Humans
  • Immunological Synapses / physiology*
  • Jurkat Cells
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Phosphorylation
  • Protein Transport
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / physiology
  • Signal Transduction / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Receptors, Antigen, T-Cell
  • UNC119 protein, human
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • ADP-Ribosylation Factors
  • ARL3 protein, human