The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface
The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface
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DOI：
10.1093/hmg/ddw230
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发表时间：
2016-09-01
影响因子：
3.5
通讯作者：
Kuehnisch, Jirko
中科院分区：
文献类型：
--
作者：
Seifert, Wenke;Posor, York;Kuehnisch, Jirko
进行性强直基因 ANKH 的显性或隐性突变与家族性软骨钙质沉着症 (CCAL2)、颅骨干骺端发育不良 (CMD)、智力低下、耳聋和强直综合征 (MRDA) 有关。所编码的膜蛋白 ANK 在质膜以外的细胞区室中的功能尚不清楚。在这里，我们发现 ANK 定位于跨高尔基体网络 (TGN)、网格蛋白包被的囊泡和质膜。 ANK 在功能上与网格蛋白和网格蛋白相关衔接蛋白 (AP) 复合物相互作用，因为任一蛋白的丢失都会导致 ANK 从 TGN 分散到细胞质内体样斑点。与其亚细胞定位一致，ANK 的缺失会导致 TGN 管状膜载体的形成减少、早期核内体的核周积累以及转铁蛋白内吞作用受损。我们的数据表明网格蛋白/AP介导的TGN、内体和细胞表面之间的ANK循环调节TGN/内体界面的膜运输。这些发现表明高尔基体-内体膜交通功能障碍可能导致 ANKH 相关病理。
Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked to familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), mental retardation, deafness and ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic endosome-like puncta. Consistent with its subcellular localization, loss of ANK results in reduced formation of tubular membrane carriers from the TGN, perinuclear accumulation of early endosomes and impaired transferrin endocytosis. Our data indicate that clathrin/AP-mediated cycling of ANK between the TGN, endosomes, and the cell surface regulates membrane traffic at the TGN/endosomal interface. These findings suggest that dysfunction of Golgi-endosomal membrane traffic may contribute to ANKH-associated pathologies.