Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice. Nat Commun 2014 Sep 02;5:4691
Date
09/03/2014Pubmed ID
25178411Pubmed Central ID
PMC4369914DOI
10.1038/ncomms5691Scopus ID
2-s2.0-84907339485 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Min SH, Suzuki A, Stalker TJ, Zhao L, Wang Y, McKennan C, Riese MJ, Guzman JF, Zhang S, Lian L, Joshi R, Meng R, Seeholzer SH, Choi JK, Koretzky G, Marks MS, Abrams CSMESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Body Weight
Cytoplasmic Granules
Endosomes
Gene Expression Regulation
Infertility
Inflammation
Longevity
Lysosomal Storage Diseases
Lysosomes
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphatidylinositol 3-Kinases
Phosphatidylinositol Phosphates
Platelet Count
Signal Transduction
Thrombosis
