Altered Clathrin-Independent Endocytosis in Type A Niemann-Pick Disease Cells and Rescue by ICAM-1-Targeted Enzyme Delivery.
Altered Clathrin-Independent Endocytosis in Type A Niemann-Pick Disease Cells and Rescue by ICAM-1-Targeted Enzyme Delivery.
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改变 A 型尼曼匹克病细胞中网格蛋白独立的内吞作用并通过 ICAM-1 靶向酶递送进行拯救。
DOI：
10.1021/mp5005959
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发表时间：
2015
影响因子：
4.9
通讯作者：
Muro,Silvia
中科院分区：
文献类型：
--
作者：
Rappaport,Jeff;Manthe,RachelL;Garnacho,Carmen;Muro,Silvia
药物干预通常需要治疗剂和/或其载体通过内吞作用进入细胞。因此，疾病引起的内吞异常是设计治疗策略时一个关键但经常被忽视的参数。对于溶酶体贮积病（lsd），其特征是溶酶体积聚未降解物质，常见的临床干预依赖于重组酶的内吞作用。然而，这些疾病的溶酶体缺陷可以影响内吞作用，正如我们最近在A型尼曼-皮克病（NPD）患者成纤维细胞中发现的网状蛋白介导的摄取，这种疾病的特征是酸性鞘磷脂酶（ASM）缺乏和随后的鞘磷脂储存。使用类似的细胞，我们已经检查了网格蛋白独立途径是否也是如此，包括小泡介导的内吞作用和巨噬细胞作用。我们观察到，相对于野生型成纤维细胞，NPD中配体结合位点的小窝蛋白-1富集受损，这与两种途径对配体和液相标记物的摄取改变相对应。同样，通过药物手段诱导的鞘磷脂的异常溶酶体储存也减少了摄取。非靶向重组ASM部分降解溶酶体储存导致部分摄取增强，而使用特异性靶向细胞间粘附分子-1的模型聚合物纳米载体ASM递送后，这两个参数都恢复到野生型水平。携带者还恢复了配体结合位点的小泡蛋白-1富集以及通过小泡和巨噬细胞途径的摄取。这些结果表明NPD的溶酶体储存与网格蛋白非依赖性内吞作用的改变之间存在联系，这可能适用于其他lsd。因此，这项研究将指导使用可行的内吞途径的治疗方法的设计。
Pharmaceutical intervention often requires therapeutics and/or their carriers to enter cells via endocytosis. Therefore, endocytic aberrancies resulting from disease represent a key, yet often overlooked, parameter in designing therapeutic strategies. In the case of lysosomal storage diseases (LSDs), characterized by lysosomal accumulation of undegraded substances, common clinical interventions rely on endocytosis of recombinant enzymes. However, the lysosomal defect in these diseases can affect endocytosis, as we recently demonstrated for clathrin-mediated uptake in patient fibroblasts with type A Niemann-Pick disease (NPD), a disorder characterized by acid sphingomylinase (ASM) deficiency and subsequent sphingomyelin storage. Using similar cells, we have examined if this is also the case for clathrin-independent pathways, including caveolae-mediated endocytosis and macropinocytosis. We observed impaired caveolin-1 enrichment at ligand-binding sites in NPD relative to wild type fibroblasts, corresponding with altered uptake of ligands and fluid-phase markers by both pathways. Similarly, aberrant lysosomal storage of sphingomyelin induced by pharmacological means also diminished uptake. Partial degradation of the lysosomal storage by untargeted recombinant ASM led to partial uptake enhancement, whereas both parameters were restored to wild type levels by ASM delivery using model polymer nanocarriers specifically targeted to intercellular adhesion molecule-1. Carriers also restored caveolin-1 enrichment at ligand-binding sites and uptake through the caveolar and macropinocytic routes. These results demonstrate a link between lysosomal storage in NPD and alterations in clathrin-independent endocytosis, which could apply to other LSDs. Hence, this study shall guide the design of therapeutic approaches using viable endocytic pathways.
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DOI：
10.1016/j.jconrel.2010.10.031
发表时间：
2011-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Hsu J;Serrano D;Bhowmick T;Kumar K;Shen Y;Kuo YC;Garnacho C;Muro S
通讯作者：
Muro S
DOI：
10.1016/j.jconrel.2011.09.067
发表时间：
2012-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Bhowmick T;Berk E;Cui X;Muzykantov VR;Muro S
通讯作者：
Muro S
细胞表面神经酰胺控制转铁蛋白受体易位至网格蛋白包被的凹坑。
影响因子：
4.8
作者：
Abo Bakr Abdel Shakor;M. Atia;K. Kwiatkowska;A. Sobota
通讯作者：
A. Sobota
靶向ICAM-1对内皮细胞上的球形载体的流动动力学，结合和脱离。
影响因子：
1.1
作者：
Calderon AJ;Muzykantov V;Muro S;Eckmann DM
通讯作者：
Eckmann DM
影响因子：
12.4
作者：
Muro, S;Schuchman, EH;Muzykantov, VR
通讯作者：
Muzykantov, VR