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The ciliary machinery is repurposed for T cell immune synapse trafficking of LCK

DOI: 10.1016/j.devcel.2018.08.012 DOI Help

Authors: Louise A. Stephen (CR-UK Beatson Institute) , Yasmin Elmaghloob (CR-UK Beatson Institute; University of Glasgow) , Michael J. Mcilwraith (CR-UK Beatson Institute) , Tamas Yelland (CR-UK Beatson Institute) , Patricia Castro Sanchez (Universidad Complutense de Madrid) , Pedro Roda-Navarro (Universidad Complutense de Madrid) , Shehab Ismail (CR-UK Beatson Institute; University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Developmental Cell , VOL 47 , PAGES 122 - 132.e4

State: Published (Approved)
Published: October 2018

Open Access Open Access

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.

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

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 11/10/2018 15:25

Documents:
1-s2.0-S1534580718306828-main.pdf

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)