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A zinc transporter, transmembrane protein 163, is critical for the biogenesis of platelet dense granules

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机构： [1]Beijing Key Laboratory for Genetics of Birth Defects/Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center/National Center for Children’s Health, and Beijing Children’s Hospital/Capital Medical University, Beijing, China [2]University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China [3]Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing, China [4]Shunyi Women and Children’s Hospital of Beijing Children’s Hospital, Beijing, China [5]State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [6]Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China

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Lysosome-related organelles (LROs) are a category of secretory organelles enriched with ions such as Ca2+, which are maintained by ion transporters or channels. Homeostasis of these ions is important for LRO biogenesis and secretion. Hermansky-Pudlak syndrome (HPS) is a recessive disorder with defects in multiple LROs, typically platelet dense granules (DGs) and melanosomes. However, the underlying mechanism of DG deficiency is largely unknown. Using quantitative proteomics, we identified a previously unreported platelet Zn2+ transporter TMEM163, which was significantly reduced in BLOC-1 (Dtnbp1 sdy and Pldn pa), BLOC-2 (Hps6 ru) or AP-3 (Ap3b1 pe) deficient mice and HPS patients (HPS2, 3, 5, 6, or 9). We observed similar platelet DG defects and abnormal intracellular zinc accumulation in platelets of mice deficient in either TMEM163 or dysbindin (a BLOC-1 subunit). In addition, we discovered that BLOC-1 was required for the trafficking of TMEM163 to perinuclear DG and late endosome (LE) marker-positive compartments (likely DG precursors) in MEG-01 cells. Our results suggest that TMEM163 is critical for DG biogenesis and BLOC-1 is required for the trafficking of TMEM163 to putative DG precursors. These new findings suggest that loss of TMEM163 function results in disruption of intracellular zinc homeostasis, and provide insights into the pathogenesis of HPS or platelet storage pool deficiency. Copyright © 2021 American Society of Hematology.

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出版当年[2020]版：

大类 | 1 区

医学

小类 | 1 区血液学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区血液学

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出版当年[2019]版：

Q1 HEMATOLOGY

最新[2023]版：

Q1 HEMATOLOGY

影响因子： 21.1 最新[2023版] 19.2 最新五年平均 17.794 出版当年[2019版] 14.892 出版当年五年平均 16.601 出版前一年[2018版] 23.629 出版后一年[2020版]

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第一作者机构： [1]Beijing Key Laboratory for Genetics of Birth Defects/Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center/National Center for Children’s Health, and Beijing Children’s Hospital/Capital Medical University, Beijing, China [2]University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

通讯作者：

通讯机构： [1]Beijing Key Laboratory for Genetics of Birth Defects/Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center/National Center for Children’s Health, and Beijing Children’s Hospital/Capital Medical University, Beijing, China [4]Shunyi Women and Children’s Hospital of Beijing Children’s Hospital, Beijing, China [*1]Beijing Children’s Hospital, Capital Medical University, 56 Nan Li Shi Rd, Xicheng District, Beijing 100045, China

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