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The functional roles of arrestin domain-containing protein 3 in regulating G protein-coupled receptor trafficking and signaling.

机译：包含restarin域的蛋白质3在调节G蛋白偶联受体的运输和信号传导中的功能作用。

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摘要

Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian beta-arrestin family, which is predicted to share similar tertiary structure with visual-/beta-arrestins and also contains C-terminal PPxY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here we focused on characterizing the role of ARRDC3 in regulating the trafficking of the beta2-adrenergic receptor (beta2AR).;Using confocal and total internal reflection fluorescence microscopy (TIR-FM) in fixed and live cells, we find that both overexpressed and endogenous ARRDC3 primarily localizes to EEA1-positive early endosomes, where it also interacts with the ESCRT-0 complex. While the PPxY motifs of ARRDC3 are essential for its endosomal localization, only one PPxY motif as well as the arrestin-like domains are needed for proper localization.;Using three approaches, both in vitro and in cells, we found that ARRDC3 directly interacts with the beta2AR in a ligand-independent manner. Functionally, while ARRDC3 has no effect on beta2AR endocytosis or degradation, it negatively regulates agonist-promoted beta2AR recycling from early endosomes to the plasma membrane. Further mechanistic studies, using fluorescent microscopy in both fixed and live cells, suggest that ARRDC3 negatively modulates beta2AR entry into SNX27-occupied endosomal tubules by regulating the association between the beta2AR and SNX27.;Concomitantly, by modulating the endosomal residence time of the beta2AR, ARRDC3 regulates the recruitment of Galphas to the receptor-occupied endosomes and the beta2AR--dependent signaling from the endosomes. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the beta2AR. Future studies should focus on identifying the interacting motifs of the beta2AR and ARRDC3, as well as expanding additional interacting partners of ARRDC3, such as additional GPCRs.
机译：含Arrestin域的蛋白质3（ARRDC3）是哺乳动物β-arrestin家族的成员，预计与视觉/β-arrestin具有相似的三级结构，并且还包含C端PPxY基序，可介导与E3泛素连接酶的相互作用。 。最近，尽管缺乏对这一过程的机械学见解，但已提出ARRDC3在调节G蛋白偶联受体的运输中起一定作用。在这里，我们着重于表征ARRDC3在调节β2-肾上腺素受体（beta2AR）的运输中的作用;;在固定和活细胞中使用共聚焦和全内反射荧光显微镜（TIR-FM），我们发现过表达和内源性ARRDC3主要定位于EEA1阳性的早期内体，并与ESCRT-0复合物相互作用。虽然ARRDC3的PPxY基序对于其内体定位至关重要，但只需要一个PPxY基序以及抑制蛋白样结构域即可正确定位。;使用体外和细胞内三种方法，我们发现ARRDC3与beta2AR以配体独立的方式。在功能上，尽管ARRDC3对beta2AR的内吞作用或降解没有影响，但它负面调节了激动剂促进的beta2AR从早期内体到质膜的再循环。在固定和活细胞中使用荧光显微镜进行的进一步机理研究表明，ARRDC3通过调节beta2AR和SNX27之间的缔合来负调节beta2AR进入SNX27占据的内体小管;同时，通过调节beta2AR的内体停留时间， ARRDC3调节Galphas向受体占据的内体的募集以及内体的beta2AR依赖性信号传导。因此，ARRDC3充当调节内体停留时间和随后的beta2AR细胞内信号转导的开关。未来的研究应侧重于确定beta2AR和ARRDC3的相互作用基序，以及扩展ARRDC3的其他相互作用伙伴，例如其他GPCR。

著录项

  • 作者

    Tian, Xufan.;

  • 作者单位

    Thomas Jefferson University.;

  • 授予单位 Thomas Jefferson University.;
  • 学科 Cellular biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 124 p.
  • 总页数 124
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 财务管理、经济核算;
  • 关键词

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