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Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse

Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse
Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. Individuals with HPS type 2 (HPS2) lack the cytosolic adaptor protein 3 (AP-3) involved in lysosomal sorting, and are also immunodeficient. Here we characterize an HPS2 mutation and demonstrate that AP-3 deficiency leads to a loss of cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Although the lysosomal protein CD63 was mislocalized to the plasma membrane, perforin and granzymes were correctly localized to the lytic granules in AP-3-deficient CTLs. However, the lytic granules of AP-3-deficient CTLs were enlarged and were unable to move along microtubules and dock within the secretory domain of the immunological synapse. These data show that AP-3 is essential for polarized secretion from CTLs.
1529-2908
1111-1120
Clark, Richard H.
dbd93f5d-393f-48f4-946b-c376a6b8b7f3
Stinchcombe, Jane C.
97a07bec-5e29-4521-9fa2-bd46cd36332c
Day, Anna
5210948e-3ea8-47eb-9be1-943c1ea65ed2
Blott, Emma
171815d2-3922-40ae-9695-1dde1b723f4a
Booth, Sarah
ff51dbbe-7bb9-47df-ba76-295753fd03a9
Bossi, Giovanna
500b9f65-a85c-4060-a57c-ad41d27b6ff5
Hamblin, Terry
d1c0d3d4-8ce7-41c1-a5a5-055b72ad073e
Davies, E. Graham
a42bc8e7-8900-4937-8a8f-cae0b7f91725
Griffiths, Gillian M.
6ee96db6-86ca-401f-93b0-701aec9aa473
Clark, Richard H.
dbd93f5d-393f-48f4-946b-c376a6b8b7f3
Stinchcombe, Jane C.
97a07bec-5e29-4521-9fa2-bd46cd36332c
Day, Anna
5210948e-3ea8-47eb-9be1-943c1ea65ed2
Blott, Emma
171815d2-3922-40ae-9695-1dde1b723f4a
Booth, Sarah
ff51dbbe-7bb9-47df-ba76-295753fd03a9
Bossi, Giovanna
500b9f65-a85c-4060-a57c-ad41d27b6ff5
Hamblin, Terry
d1c0d3d4-8ce7-41c1-a5a5-055b72ad073e
Davies, E. Graham
a42bc8e7-8900-4937-8a8f-cae0b7f91725
Griffiths, Gillian M.
6ee96db6-86ca-401f-93b0-701aec9aa473

Clark, Richard H., Stinchcombe, Jane C., Day, Anna, Blott, Emma, Booth, Sarah, Bossi, Giovanna, Hamblin, Terry, Davies, E. Graham and Griffiths, Gillian M. (2003) Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nature Immunology, 4 (11), 1111-1120. (doi:10.1038/ni1000).

Record type: Article

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. Individuals with HPS type 2 (HPS2) lack the cytosolic adaptor protein 3 (AP-3) involved in lysosomal sorting, and are also immunodeficient. Here we characterize an HPS2 mutation and demonstrate that AP-3 deficiency leads to a loss of cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Although the lysosomal protein CD63 was mislocalized to the plasma membrane, perforin and granzymes were correctly localized to the lytic granules in AP-3-deficient CTLs. However, the lytic granules of AP-3-deficient CTLs were enlarged and were unable to move along microtubules and dock within the secretory domain of the immunological synapse. These data show that AP-3 is essential for polarized secretion from CTLs.

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Published date: 2003

Identifiers

Local EPrints ID: 26246
URI: http://eprints.soton.ac.uk/id/eprint/26246
ISSN: 1529-2908
PURE UUID: 52a89f3b-de19-49f8-8ae6-1fded1d111f6

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Date deposited: 24 Apr 2006
Last modified: 27 Apr 2022 08:45

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Contributors

Author: Richard H. Clark
Author: Jane C. Stinchcombe
Author: Anna Day
Author: Emma Blott
Author: Sarah Booth
Author: Giovanna Bossi
Author: Terry Hamblin
Author: E. Graham Davies
Author: Gillian M. Griffiths

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