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J Cell Biol. 2015 Jul 6;210(1):135-51. doi: 10.1083/jcb.201411093. Epub 2015 Jun 29.

VAMP8-dependent fusion of recycling endosomes with the plasma membrane facilitates T lymphocyte cytotoxicity.

Author information

1
Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, 66421 Homburg, Germany Department of Medicine, Center For Infectious Medicine, 14186 Stockholm, Sweden.
2
Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, 66421 Homburg, Germany.
3
Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, 66421 Homburg, Germany Department of Pathology, Brigham and Woman's Hospital, Boston, MA.
4
Department of Medicine, Center For Infectious Medicine, 14186 Stockholm, Sweden.
5
Membrane Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673.
6
Department of Biophysics, Saarland University, 66421 Homburg, Germany.
7
Department of Anatomy, Saarland University, 66421 Homburg, Germany.
8
Department of Medicine, Center For Infectious Medicine, 14186 Stockholm, Sweden jrettig@uks.eu Yenan.Bryceson@ki.se.
9
Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, 66421 Homburg, Germany jrettig@uks.eu Yenan.Bryceson@ki.se.

Abstract

Cytotoxic T lymphocytes (CTLs) eliminate infected and neoplastic cells through directed release of cytotoxic granule contents. Although multiple SNARE proteins have been implicated in cytotoxic granule exocytosis, the role of vesicular SNARE proteins, i.e., vesicle-associated membrane proteins (VAMPs), remains enigmatic. VAMP8 was posited to represent the cytotoxic granule vesicular SNARE protein mediating exocytosis in mice. In primary human CTLs, however, VAMP8 colocalized with Rab11a-positive recycling endosomes. Upon stimulation, these endosomes rapidly trafficked to and fused with the plasma membrane, preceding fusion of cytotoxic granules. Knockdown of VAMP8 blocked both recycling endosome and cytotoxic granule fusion at immune synapses, without affecting activating signaling. Mechanistically, VAMP8-dependent recycling endosomes deposited syntaxin-11 at immune synapses, facilitating assembly of plasma membrane SNARE complexes for cytotoxic granule fusion. Hence, cytotoxic granule exocytosis is a sequential, multivesicle fusion process requiring VAMP8-mediated recycling endosome fusion before cytotoxic granule fusion. Our findings imply that secretory granule exocytosis pathways in other cell types may also be more complex than previously appreciated.

PMID:
26124288
PMCID:
PMC4493996
DOI:
10.1083/jcb.201411093
[Indexed for MEDLINE]
Free PMC Article

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