SLC35D3 delivery from megakaryocyte early endosomes is required for platelet dense granule biogenesis and is differentially defective in Hermansky-Pudlak syndrome models
Open Access
- 12 July 2012
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 120 (2), 404-414
- https://doi.org/10.1182/blood-2011-11-389551
Abstract
Platelet dense granules are members of a family of tissue-specific, lysosome-related organelles that also includes melanosomes in melanocytes. Contents released from dense granules after platelet activation promote coagulation and hemostasis, and dense granule defects such as those seen in Hermansky-Pudlak syndrome (HPS) cause excessive bleeding, but little is known about how dense granules form in megakaryocytes (MKs). In the present study, we used SLC35D3, mutation of which causes a dense granule defect in mice, to show that early endosomes play a direct role in dense granule biogenesis. We show that SLC35D3 expression is up-regulated during mouse MK differentiation and is enriched in platelets. Using immunofluorescence and immunoelectron microscopy and subcellular fractionation in megakaryocytoid cells, we show that epitope-tagged and endogenous SLC35D3 localize predominantly to early endosomes but not to dense granule precursors. Nevertheless, SLC35D3 is depleted in mouse platelets from 2 of 3 HPS models and, when expressed ectopically in melanocytes, SLC35D3 localizes to melanosomes in a manner requiring a HPS-associated protein complex that functions from early endosomal transport intermediates. We conclude that SLC35D3 is either delivered to nascent dense granules from contiguous early endosomes as MKs mature or functions in dense granule biogenesis directly from early endosomes, suggesting that dense granules originate from early endosomes in MKs.This publication has 59 references indexed in Scilit:
- Disorders of Lysosome-Related Organelle Biogenesis: Clinical and Molecular GeneticsAnnual Review of Genomics and Human Genetics, 2008
- Melanosomes — dark organelles enlighten endosomal membrane transportNature Reviews Molecular Cell Biology, 2007
- Lysosome-related organelles: driving post-Golgi compartments into specialisationCurrent Opinion in Cell Biology, 2007
- BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related OrganellesMolecular Biology of the Cell, 2007
- The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granulesBlood, 2006
- Maturation stage–specific regulation of megakaryopoiesis by pointed-domain Ets proteinsBlood, 2006
- BLOC-1 Interacts with BLOC-2 and the AP-3 Complex to Facilitate Protein Trafficking on EndosomesMolecular Biology of the Cell, 2006
- BLOC-1 Complex Deficiency Alters the Targeting of Adaptor Protein Complex-3 CargoesMolecular Biology of the Cell, 2006
- Plat-E: an efficient and stable system for transient packaging of retrovirusesGene Therapy, 2000
- The empty sack syndrome: a platelet storage pool deficiency associated with empty dense granulesBritish Journal of Haematology, 1994