ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting
ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting
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DOI：
10.1073/pnas.1210916109
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发表时间：
2012-11-27
影响因子：
11.1
通讯作者：
Seo, Seongjin
中科院分区：
文献类型：
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作者：
Humbert, Melissa C.;Weihbrecht, Katie;Seo, Seongjin
影响纤毛成分的突变在人类中引起一系列相关的遗传疾病，包括肾单位萎缩症（NPHP）、Joubert综合征（JBTS）、Meckel-Gruber综合征（MKS）和Bardet-Biedl综合征（BBS），这些综合征统称为“纤毛病"。“最近的蛋白质-蛋白质相互作用研究结合遗传分析显示，纤毛病相关蛋白质形成了几个功能网络/模块，构建和维持初级纤毛。然而，许多纤毛病相关蛋白的确切功能和这些蛋白靶向初级纤毛的机制仍然没有很好地理解。在这里，我们描述了一个蛋白质-蛋白质相互作用网络的肌醇多磷酸-5-磷酸酶E（INPP 5E），异戊二烯化的蛋白质与JBTS，及其纤毛靶向机制。INPP 5E通过C末端附近的基序和异戊烯基结合蛋白磷酸二酯酶6D（PDE 6D）依赖性机制靶向初级纤毛。INPP 5E的纤毛靶向由另一种JBTS蛋白ADP-核糖基化因子样13 B（ARL 13 B）促进，但不由ARL 2或ARL 3促进。导致人类JBTS的ARL 13 B错义突变破坏了ARL 13 B-INPP 5E相互作用。我们进一步证明了INPP 5E与几种纤毛和中心体蛋白的相互作用，包括最近鉴定的纤毛病蛋白中心体蛋白164（CEP 164）。这些发现表明，ARL 13 B，INPP 5E，PDE 6D和CEP 164形成了一个独特的功能网络，参与JBTS和NPHP，但独立于先前由NPHP和MKS蛋白定义的功能网络。
Mutations affecting ciliary components cause a series of related genetic disorders in humans, including nephronophthisis (NPHP), Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), and Bardet-Biedl syndrome (BBS), which are collectively termed "ciliopathies." Recent protein-protein interaction studies combined with genetic analyses revealed that ciliopathy-related proteins form several functional networks/modules that build and maintain the primary cilium. However, the precise function of many ciliopathy-related proteins and the mechanisms by which these proteins are targeted to primary cilia are still not well understood. Here, we describe a protein-protein interaction network of inositol polyphosphate-5-phosphatase E (INPP5E), a prenylated protein associated with JBTS, and its ciliary targeting mechanisms. INPP5E is targeted to the primary cilium through a motif near the C terminus and prenyl-binding protein phosphodiesterase 6D (PDE6D)-dependent mechanisms. Ciliary targeting of INPP5E is facilitated by another JBTS protein, ADP-ribosylation factor-like 13B (ARL13B), but not by ARL2 or ARL3. ARL13B missense mutations that cause JBTS in humans disrupt the ARL13B-INPP5E interaction. We further demonstrate interactions of INPP5E with several ciliary and centrosomal proteins, including a recently identified ciliopathy protein centrosomal protein 164 (CEP164). These findings indicate that ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network that is involved in JBTS and NPHP but independent of the ones previously defined by NPHP and MKS proteins.