論文 - 詳細
| RRC ID | 57317 |
|---|---|
| 著者 | Ohishi Y, Kinoshita R, Marubashi S, Ishida M, Fukuda M. |
| タイトル | The BLOC-3 subunit HPS4 is required for activation of Rab32/38 GTPases in melanogenesis, but its Rab9 activity is dispensable for melanogenesis. |
| ジャーナル | J Biol Chem |
| Abstract |
HPS4 biogenesis of lysosome-related organelles complex 3 subunit 2 (HPS4) is one of the genes whose mutations have been associated with Hermansky-Pudlak syndrome (HPS), characterized by ocular albinism and susceptibility to bleeding because of defects in the biogenesis of lysosome-related organelles such as melanosomes. HPS4 protein forms a BLOC-3 complex with HPS1, another HPS gene product, and the complex has been proposed to function as a guanine nucleotide exchange factor (GEF) for RAB32, a member of the Rab small GTPase family (Rab32), and Rab38 (Rab32/38-GEF) and also as a Rab9 effector. Although both Rab32/38 and Rab9 have been shown previously to be involved in melanogenesis in mammalian epidermal melanocytes, the functional relationships of these small GTPases with BLOC-3 remain unknown. In this study, we used site-directed mutagenesis to generate HPS4 mutants that specifically lack either Rab32/38-GEF activity or Rab9-binding activity and investigated their involvement in melanogenesis of melan-le cells (an HPS4-deficient melanocyte cell line derived from light ear mice). Melan-le cells exhibit a clear hypopigmentation phenotype, i.e. reduced expression and abnormal distribution of tyrosinase and reduced melanin content. Although re-expression of WT HPS4 completely rescued this phenotype, the Rab32/38-GEF activity-deficient HPS4 mutant failed to restore melanin content and tyrosinase trafficking in these cells. Unexpectedly, as WT HPS4, the Rab9 binding-deficient HPS4 mutant completely rescued the phenotype. These results indicate that activation of Rab32/38 by HPS4 (or BLOC-3) is essential for melanogenesis of cultured melanocytes and that Rab9 likely regulates melanogenesis independently of HPS4. |
| 巻・号 | 294(17) |
| ページ | 6912-6922 |
| 公開日 | 2019-4-26 |
| DOI | 10.1074/jbc.RA119.007345 |
| PII | S0021-9258(20)36625-4 |
| PMID | 30837268 |
| PMC | PMC6497944 |
| MeSH | Amino Acid Sequence Animals COS Cells Cell Line, Transformed Chlorocebus aethiops Enzyme Activation Guanine Nucleotide Exchange Factors / chemistry Guanine Nucleotide Exchange Factors / physiology* Melanins / biosynthesis* Mice Mutagenesis, Site-Directed Protein Binding rab GTP-Binding Proteins / metabolism* |
| IF | 4.106 |
| 引用数 | 1 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | pEF-T7-HPS4(S541A/N543A) (RDB17367) pEF-T7-HPS4(G55W/G59M) (RDB17368) pEF-FLAG-HPS1 (RDB17369) pGBD-C1-Rab6D-deltaCys-T45N (RDB17399) pGBD-C1-Rab40AL-deltaCys-S28N (RDB17444) pGBD-C1-Rab6D-deltaCys-Q89L (RDB18834) pGBD-C1-Rab40AL-deltaCys-Q73L (RDB18924) |