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

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

Author information

1
CR-UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2
CR-UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
3
Department of Immunology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain; 12 de Octubre Health Research Institute (imas12), Madrid 28040, Spain.
4
CR-UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: s.ismail@beatson.gla.ac.uk.

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

PMID:
30220567
PMCID:
PMC6179904
DOI:
10.1016/j.devcel.2018.08.012
[Indexed for MEDLINE]
Free PMC Article

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