Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice

Sang H. Min, Aae Suzuki, Timothy J. Stalker, Liang Zhao, Yuhuan Wang, Chris McKennan, Matthew J. Riese, Jessica F. Guzman, Suhong Zhang, Lurong Lian, Rohan Joshi, Ronghua Meng, Steven H. Seeholzer, John K. Choi, Gary Koretzky, Michael S. Marks and Charles S. Abrams ()
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Sang H. Min: University of Pennsylvania School of Medicine
Aae Suzuki: University of Pennsylvania School of Medicine
Timothy J. Stalker: University of Pennsylvania School of Medicine
Liang Zhao: University of Pennsylvania School of Medicine
Yuhuan Wang: The Children’s Hospital of Philadelphia
Chris McKennan: Proteomics Core, The Children’s Hospital of Philadelphia
Matthew J. Riese: University of Pennsylvania School of Medicine
Jessica F. Guzman: University of Pennsylvania School of Medicine
Suhong Zhang: University of Pennsylvania School of Medicine
Lurong Lian: University of Pennsylvania School of Medicine
Rohan Joshi: University of Pennsylvania School of Medicine
Ronghua Meng: The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine
Steven H. Seeholzer: Proteomics Core, The Children’s Hospital of Philadelphia
John K. Choi: St Jude Children's Research Hospital
Gary Koretzky: University of Pennsylvania School of Medicine
Michael S. Marks: The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine
Charles S. Abrams: University of Pennsylvania School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5691

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