title: Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice.
abstract: PIKfyve is essential for the synthesis of phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and for the regulation of endolysosomal membrane dynamics in mammals. PtdIns(3,5)P2 deficiency causes neurodegeneration in mice and humans, but the role of PtdIns(3,5)P2 in non-neural tissues is poorly understood. Here we show that platelet-specific ablation of PIKfyve in mice leads to accelerated arterial thrombosis, and, unexpectedly, also to inappropriate inflammatory responses characterized by macrophage accumulation in multiple tissues. These multiorgan defects are attenuated by platelet depletion in vivo, confirming that they reflect a platelet-specific process. PIKfyve ablation in platelets induces defective maturation and excessive storage of lysosomal enzymes that are released upon platelet activation. Impairing lysosome secretion from PIKfyve-null platelets in vivo markedly attenuates the multiorgan defects, suggesting that platelet lysosome secretion contributes to pathogenesis. Our findings identify PIKfyve as an essential regulator for platelet lysosome homeostasis, and demonstrate the contributions of platelet lysosomes to inflammation, arterial thrombosis and macrophage biology.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sang H
authors.initials: SH
authors.lastname: Min
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Aae
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stalker
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Proteomics Core, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: McKennan
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Riese
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Guzman
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Suhong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lurong
authors.initials: L
authors.lastname: Lian
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rohan
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Meng
authors.affiliation: Proteomics Core, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Seeholzer
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Koretzky
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Abrams
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology / Q000473:pathology*; D001835:Body Weight; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000473:pathology; D011992:Endosomes / Q000201:enzymology / Q000473:pathology*; D005786:Gene Expression Regulation; D007246:Infertility / Q000235:genetics; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000473:pathology; D008136:Longevity / Q000235:genetics; D016464:Lysosomal Storage Diseases / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010976:Platelet Count; D015398:Signal Transduction; D013927:Thrombosis / Q000150:complications / Q000201:enzymology / Q000473:pathology*
chemical_list: D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D019869:Phosphatidylinositol 3-Kinases; C116930:Pikfyve protein, mouse