دورية أكاديمية
NPC1 plays a role in the trafficking of specific cargo to melanosomes.
| العنوان: | NPC1 plays a role in the trafficking of specific cargo to melanosomes. |
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| المؤلفون: | Rus AA; Department of Molecular Cell Biology, Institute of Biochemistry, Bucharest, Romania., Militaru IV; Department of Molecular Cell Biology, Institute of Biochemistry, Bucharest, Romania., Popa I; Department of Molecular Cell Biology, Institute of Biochemistry, Bucharest, Romania., Munteanu CVA; Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry, Bucharest, Romania., Sima LE; Department of Molecular Cell Biology, Institute of Biochemistry, Bucharest, Romania., Platt N; Department of Pharmacology, University of Oxford, Oxford, UK., Platt FM; Department of Pharmacology, University of Oxford, Oxford, UK., Petrescu ȘM; Department of Molecular Cell Biology, Institute of Biochemistry, Bucharest, Romania. Electronic address: stefana.petrescu@biochim.ro. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2023 Aug; Vol. 299 (8), pp. 105024. Date of Electronic Publication: 2023 Jul 07. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Niemann-Pick Diseases*/genetics , Niemann-Pick Diseases*/metabolism , Niemann-Pick Disease, Type C*/metabolism, Humans ; Melanosomes/metabolism ; Monophenol Monooxygenase/metabolism ; Niemann-Pick C1 Protein/metabolism ; Cholesterol/metabolism |
| مستخلص: | Niemann-Pick type C1 (NPC1) protein is a multimembrane spanning protein of the lysosome limiting membrane that facilitates intracellular cholesterol and sphingolipid transport. Loss-of-function mutations in the NPC1 protein cause Niemann-Pick disease type C1, a lysosomal storage disorder characterized by the accumulation of cholesterol and sphingolipids within lysosomes. To investigate whether the NPC1 protein could also play a role in the maturation of the endolysosomal pathway, here, we have investigated its role in a lysosome-related organelle, the melanosome. Using a NPC1-KO melanoma cell model, we found that the cellular phenotype of Niemann-Pick disease type C1 is associated with a decreased pigmentation accompanied by low expression of the melanogenic enzyme tyrosinase. We propose that the defective processing and localization of tyrosinase, occurring in the absence of NPC1, is a major determinant of the pigmentation impairment in NPC1-KO cells. Along with tyrosinase, two other pigmentation genes, tyrosinase-related protein 1 and Dopachrome-tautomerase have lower protein levels in NPC1 deficient cells. In contrast with the decrease in pigmentation-related protein expression, we also found a significant intracellular accumulation of mature PMEL17, the structural protein of melanosomes. As opposed to the normal dendritic localization of melanosomes, the disruption of melanosome matrix generation in NPC1 deficient cells causes an accumulation of immature melanosomes adjacent to the plasma membrane. Together with the melanosomal localization of NPC1 in WT cells, these findings suggest that NPC1 is directly involved in tyrosinase transport from the trans-Golgi network to melanosomes and melanosome maturation, indicating a novel function for NPC1. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| معلومات مُعتمدة: | 202834/Z/16/Z United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | Keywords: NPC1; Niemann-Pick disease type C; PMEL17; endosomes; lysosome-related organelles; melanosomes biogenesis; traffic; tyrosinase |
| المشرفين على المادة: | EC 1.14.18.1 (Monophenol Monooxygenase) 0 (Niemann-Pick C1 Protein) 97C5T2UQ7J (Cholesterol) 0 (NPC1 protein, human) |
| تواريخ الأحداث: | Date Created: 20230709 Date Completed: 20230831 Latest Revision: 20240306 |
| رمز التحديث: | 20240306 |
| مُعرف محوري في PubMed: | PMC10407747 |
| DOI: | 10.1016/j.jbc.2023.105024 |
| PMID: | 37423302 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2023.105024 |