BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors.
BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors.
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DOI：
10.1038/srep11855
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发表时间：
2015-07-07
影响因子：
4.6
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Xu Q;Zhang Y;Wei Q;Huang Y;Li Y;Ling K;Hu J
纤毛为各种对脊椎动物发育至关重要的信号级联提供感觉受体。然而，睫状体感觉受体动态平衡的机制仍然是难以捉摸的。在这里，我们证明了BBS-4和BBS-5这两个不同的BBSome成分，在秀丽隐杆线虫纤毛的背景下显示出意想不到的功能冗余。BBS-4直接与BBS-5相互作用，这种相互作用可以被人类BBS4中发现的一个保守突变破坏。令人惊讶的是，我们发现BBS-4和BBS-5在BBSome中冗余地调节各种感觉受体的纤毛去除，而不是纤毛进入或逆行IFT运输。进一步的分析表明，BBS-4和BBS-5的共同耗竭破坏了睫状感觉受体的溶酶体靶向降解分选。此外，哺乳动物BBS4和BBS5也直接相互作用，协调多囊素2的纤毛去除。因此，我们揭示了一个新的和高度保守的作用，BBSome在纤毛信号的微调中，通过调节纤毛的感觉受体去除来进行溶酶体降解。
Cilia harbor sensory receptors for various signaling cascades critical for vertebrate development. However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive. Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans. BBS-4 directly interacts with BBS-5 and the interaction can be disrupted by a conserved mutation identified in human BBS4. Surprisingly, we found that BBS-4 and BBS-5 act redundantly in the BBSome to regulate the ciliary removal, rather than the ciliary entry or retrograde IFT transport, of various sensory receptors. Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors. Moreover, mammalian BBS4 and BBS5 also interact directly and coordinate the ciliary removal of polycystin 2. Hence, we reveal a novel and highly conserved role for the BBSome in fine-tuning ciliary signaling by regulating the ciliary removal of sensory receptors for lysosomal degradation.
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