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.
Clark
Richard H
RH
Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.
Stinchcombe
Jane C
JC
Day
Anna
A
Blott
Emma
E
Booth
Sarah
S
Bossi
Giovanna
G
Hamblin
Terry
T
Davies
E Graham
EG
Griffiths
Gillian M
GM
D033963:Adaptor Protein Complex 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D033966:Adaptor Protein Complex beta Subunits; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D003594:Cytoplasmic Granules / Q000378:metabolism* / Q000648:ultrastructure; D022861:Hermanski-Pudlak Syndrome / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000276:immunology / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000648:ultrastructure; D060149:Tetraspanin 30
C439973:AP3B1 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D015703:Antigens, CD; C554586:CD63 protein, human; D026901:Membrane Transport Proteins; D010980:Platelet Membrane Glycoproteins; D011506:Proteins; D060149:Tetraspanin 30