The Clathrin Adaptor Proteins ARH, Dab2, and Numb Play Distinct Roles in Niemann-Pick C1-Like 1 Versus Low Density Lipoprotein Receptor-mediated Cholesterol Uptake
文献类型：期刊论文
| 作者 | Wei, J; Fu, ZY; Li, PS; Miao, HH; Li, BL; Ma, YT; Song, BL |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
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| 出版日期 | 2014 |
| 卷号 | 289期号:48页码:33689-33700 |
| 通讯作者 | Ma, YT (reprint author), Xinjiang Med Univ, Affiliated Hosp 1, Dept Cardiovasc Med, Urumqi 830054, Peoples R China.,myt-xj@163.com ; blsong@whu.edu.cn |
| 英文摘要 | The uptake of circulating low density lipoproteins (LDL) is mediated by LDL receptor (LDLR) through clathrin-dependent endocytosis. At the early stage of this process, adaptor proteins ARH and Dab2 specifically bind the endocytic signal motif in LDLR and recruit clathrin/AP2 to initiate internalization. On the other hand, intestinal cholesterol is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) through clathrin-dependent endocytosis. Another adaptor protein, Numb recognizes the endocytic motif in NPC1L1 C terminus and couples NPC1L1 to endocytic machinery. The ARH, Dab2, and Numb proteins contain a homogeneous phosphotyrosine binding (PTB) domain that directly binds endocytic motifs. Because ARH, Dab2, and Numb are all PTB domain family members, the emerging mystery is whether these adaptors act complementally in LDLR and NPC1L1 endocytosis. Here, we found that ARH and Dab2 did not bind NPC1L1 and were not required for NPC1L1 internalization. Similarly, Numb lacked the ability to interact with the LDLR C terminus and was dispensable for LDL uptake. Only the Numb isoforms with shorter PTB domain could facilitate NPC1L1 endocytosis. Besides the reported function in intestinal cholesterol absorption, Numb also mediated cholesterol reabsorption from bile in liver. We further identified a Numb variant with G595D substitution in humans of low blood LDL-cholesterol. The G595D substitution impaired NPC1L1 internalization and cholesterol reabsorption, due to attenuating affinity of Numb to clathrin/AP2. These results demonstrate that Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake. |
| 学科主题 | Biochemistry & Molecular Biology |
| 类目[WOS] | Biochemistry & Molecular Biology |
| 关键词[WOS] | AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA ; LDL RECEPTOR ; CELL-MIGRATION ; RISK-FACTORS ; PTB DOMAIN ; INTERNALIZATION ; ENDOCYTOSIS ; DIFFERENTIATION ; PROLIFERATION ; ABSORPTION |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000345636600053 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/273]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Wei, J,Fu, ZY,Li, PS,et al. The Clathrin Adaptor Proteins ARH, Dab2, and Numb Play Distinct Roles in Niemann-Pick C1-Like 1 Versus Low Density Lipoprotein Receptor-mediated Cholesterol Uptake[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2014,289(48):33689-33700. |
| APA | Wei, J.,Fu, ZY.,Li, PS.,Miao, HH.,Li, BL.,...&Song, BL.(2014).The Clathrin Adaptor Proteins ARH, Dab2, and Numb Play Distinct Roles in Niemann-Pick C1-Like 1 Versus Low Density Lipoprotein Receptor-mediated Cholesterol Uptake.JOURNAL OF BIOLOGICAL CHEMISTRY,289(48),33689-33700. |
| MLA | Wei, J,et al."The Clathrin Adaptor Proteins ARH, Dab2, and Numb Play Distinct Roles in Niemann-Pick C1-Like 1 Versus Low Density Lipoprotein Receptor-mediated Cholesterol Uptake".JOURNAL OF BIOLOGICAL CHEMISTRY 289.48(2014):33689-33700. |
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