Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation.

Abstract:

:Fas ligand (FasL), a potent mediator of apoptosis expressed by CTL and NK cells, is sorted into the inner vesicles of secretory lysosomes for release via exosome-like vesicles. Previous studies identified a proline-rich domain in the cytoplasmic tail required for sorting FasL to secretory lysosomes, but the mechanisms by which this occurs have not been identified. Here we demonstrate that the PRD of FasL binds Fgr, Fyn and Lyn tyrosine kinases, leading to phosphorylation of FasL. Loss of phosphorylation reduces internalisation of FasL into multivesicular bodies. FasL is also directly mono-ubiquitylated at lysines flanking the PRD and mutation of these lysines reduces MVB localisation of FasL. Phosphorylation is not required for ubiquitylation because FasL lacking all tyrosines undergoes mono-ubiquitylation. These studies show that phosphorylation and ubiquitin signals regulate the sorting of FasL to secretory lysosomes by controlling entry into multivesicular bodies.

journal_name

J Cell Sci

journal_title

Journal of cell science

authors

Zuccato E,Blott EJ,Holt O,Sigismund S,Shaw M,Bossi G,Griffiths GM

doi

10.1242/jcs.03315

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

191-9

issue

Pt 1

eissn

0021-9533

issn

1477-9137

pii

jcs.03315

journal_volume

120

pub_type

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