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First published online 12 December 2006
doi: 10.1242/jcs.03315

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

Elisabetta Zuccato^1,*, Emma J. Blott^1,*, Oliver Holt¹, Sara Sigismund², Michael Shaw¹, Giovanna Bossi¹ and Gillian M. Griffiths^1,

¹ Sir William Dunn School of Pathology, South Parks Rd, Oxford, OX1 3RE, UK
² IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy

Author for correspondence (e-mail: gillian.griffiths{at}path.ox.ac.uk)

Accepted 24 October 2006

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.

Key words: Fas ligand, Multivesicular bodies, Sorting, Ubiquitylation, Phosphorylation

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