title: Defective release of α granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models.
abstract: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding diathesis, and other variable symptoms. The bleeding diathesis has been attributed to δ storage pool deficiency, reflecting the malformation of platelet dense granules. Here, we analyzed agonist-stimulated secretion from other storage granules in platelets from mouse HPS models that lack adaptor protein (AP)-3 or biogenesis of lysosome-related organelles complex (BLOC)-3 or BLOC-1. We show that α granule secretion elicited by low agonist doses is impaired in all 3 HPS models. High agonist doses or supplemental adenosine 5'-diphosphate (ADP) restored normal α granule secretion, suggesting that the impairment is secondary to absent dense granule content release. Intravital microscopy following laser-induced vascular injury showed that defective hemostatic thrombus formation in HPS mice largely reflected reduced total platelet accumulation and affirmed a reduced area of α granule secretion. Agonist-induced lysosome secretion ex vivo was also impaired in all 3 HPS models but was incompletely rescued by high agonist doses or excess ADP. Our results imply that (1) AP-3, BLOC-1, and BLOC-3 facilitate protein sorting to lysosomes to support ultimate secretion; (2) impaired secretion of α granules in HPS, and to some degree of lysosomes, is secondary to impaired dense granule secretion; and (3) diminished α granule and lysosome secretion might contribute to pathology in HPS.
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Meng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Department of Pathology and Laboratory Medicine.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Harper
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and Institute of Medical Biology, Polish Academy of Science, Lodz, Poland.
authors.forename: M Anna
authors.initials: MA
authors.lastname: Kowalska
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Charles S
authors.initials: CS
authors.lastname: Abrams
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Brass
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stalker
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Department of Pathology and Laboratory Medicine.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D015550:Cell Degranulation / Q000502:physiology; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors; D022861:Hermanski-Pudlak Syndrome / Q000097:blood* / Q000209:etiology / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008247:Lysosomes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000097:blood; D050600:SNARE Proteins / Q000097:blood; D022142:Secretory Vesicles / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D033963:Adaptor Protein Complex 3; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C507980:Hps4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D019007:P-Selectin; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins; D000244:Adenosine Diphosphate; D013917:Thrombin