Localization of a guanylyl cyclase to chemosensory cilia requires the novel ciliary MYND domain protein DAF-25.
Localization of a guanylyl cyclase to chemosensory cilia requires the novel ciliary MYND domain protein DAF-25.
复制标题
DOI：
10.1371/journal.pgen.1001199
复制
发表时间：
2010-11-24
期刊：
影响因子：
4.5
通讯作者：
Riddle DL
中科院分区：
文献类型：
--
作者：
Jensen VL;Bialas NJ;Bishop-Hurley SL;Molday LL;Kida K;Nguyen PA;Blacque OE;Molday RS;Leroux MR;Riddle DL
在恶劣的条件下，秀丽隐杆线虫停止发育，进入一种非衰老的、具有抗性的滞育状态，称为dauer幼虫。嗅觉调节TGF-β和胰岛素信号通路以控制这一发育决定。四个突变等位基因的daf-25（异常DAuer形成）从筛选的突变体表现出组成性DAuer形成，并发现有缺陷的嗅觉。daf-25 dauer表型被daf-10/IFFT 122突变（破坏纤毛发生）抑制，但不被daf-6/PTCHD3突变（阻止感觉纤毛暴露于环境）抑制，这意味着daf-25在纤毛本身中起作用。daf-25编码C.哺乳动物Ankmy2的直向同源物，一种功能未知的MYND结构域蛋白。通过光学显微镜和电子显微镜测定，定位于感觉纤毛的α-25的破坏不会产生明显的纤毛结构异常。提示其潜在的功能，daf-25的dauer表型，上位顺序和表达谱与daf-11相似，后者编码纤毛定位的鸟苷酸环化酶。事实上，我们证明，需要适当的α-11纤毛定位的α-25。此外，功能相互作用是进化保守的，因为小鼠Ankmy2与来自睫状光感受器的鸟苷酸环化酶GC 1相互作用。这种相互作用可能是特异性的，因为daf-25突变体在纤毛中具有正常定位的OSM-9/TRPV 4、TAX-4/CNGA 1、CHE-2/IFT 80、CHE-11/IFT 140、CHE-13/IFT 57、BBS-8、OSM-5/IFT 88和XBX-1/D2LIC。鞭毛内运输（IFT）（需要建立纤毛）是没有缺陷的daf-25突变体，虽然纤毛定位的daf-25本身的影响，在che-11突变体，这是有缺陷的逆行IFT。总之，我们发现了一种新的纤毛蛋白，它通过将鸟苷酸环化酶定位于感觉细胞器，在cGMP信号传导中起重要作用。 C.不能形成或阻止发育为Dauer幼虫（一种抗胁迫的生命阶段）的线虫突变体通常在涉及进化上保守的信号传导途径的基因中具有缺陷。在这项研究中，我们确定了daf-25突变株中的基因突变，这些突变株不适当地捕获了dauer幼虫，并且在嗅觉上也有缺陷。Ankmy2是一种功能未知的蛋白质，含有三个锚蛋白重复序列和一个锌指MYND结构域，这两个结构域都被预测可以结合其他蛋白质。我们发现，ESTA-25/Ankmy2是必要的膜结合的鸟苷酸环化酶的适当本地化-一类蛋白质的功能，在环GMP信号纤毛，这是保守的感觉细胞器。我们进一步证明，哺乳动物Ankmy2结合视网膜鸟苷酸环化酶GC 1，提示Ankmy2在视觉中的作用，这严重依赖于环GMP信号转导，提示Ankmy2在人类视网膜疾病中的潜在参与，以及其他纤毛相关疾病，如肥胖症。
In harsh conditions, Caenorhabditis elegans arrests development to enter a non-aging, resistant diapause state called the dauer larva. Olfactory sensation modulates the TGF-β and insulin signaling pathways to control this developmental decision. Four mutant alleles of daf-25 (abnormal DAuer Formation) were isolated from screens for mutants exhibiting constitutive dauer formation and found to be defective in olfaction. The daf-25 dauer phenotype is suppressed by daf-10/IFT122 mutations (which disrupt ciliogenesis), but not by daf-6/PTCHD3 mutations (which prevent environmental exposure of sensory cilia), implying that DAF-25 functions in the cilia themselves. daf-25 encodes the C. elegans ortholog of mammalian Ankmy2, a MYND domain protein of unknown function. Disruption of DAF-25, which localizes to sensory cilia, produces no apparent cilia structure anomalies, as determined by light and electron microscopy. Hinting at its potential function, the dauer phenotype, epistatic order, and expression profile of daf-25 are similar to daf-11, which encodes a cilium-localized guanylyl cyclase. Indeed, we demonstrate that DAF-25 is required for proper DAF-11 ciliary localization. Furthermore, the functional interaction is evolutionarily conserved, as mouse Ankmy2 interacts with guanylyl cyclase GC1 from ciliary photoreceptors. The interaction may be specific because daf-25 mutants have normally-localized OSM-9/TRPV4, TAX-4/CNGA1, CHE-2/IFT80, CHE-11/IFT140, CHE-13/IFT57, BBS-8, OSM-5/IFT88, and XBX-1/D2LIC in the cilia. Intraflagellar transport (IFT) (required to build cilia) is not defective in daf-25 mutants, although the ciliary localization of DAF-25 itself is influenced in che-11 mutants, which are defective in retrograde IFT. In summary, we have discovered a novel ciliary protein that plays an important role in cGMP signaling by localizing a guanylyl cyclase to the sensory organelle. C. elegans mutants that either fail to form or arrest development as dauer larvae, a stress-resistant lifestage, usually have defects in genes involved in evolutionarily conserved signaling pathways. In this study, we identified the gene mutated in daf-25 mutant strains, which inappropriately arrest as dauer larvae and are also defective in the sense of smell. The mammalian counterpart of DAF-25 is Ankmy2, a protein of unknown function that contains three ankyrin repeats and a zinc finger MYND domain, both of which are predicted to bind other protein(s). We show that DAF-25/Ankmy2 is required for the proper localization of a membrane-bound guanylyl cyclase—a class of protein that functions in cyclic GMP signaling—to cilia, which are conserved sensory organelles. We further demonstrate that mammalian Ankmy2 binds the retinal guanylyl cyclase GC1, suggesting a role for Ankmy2 in vision—which critically depends on cyclic GMP signal transduction—suggesting the potential involvement of Ankmy2 in human retinal disease, as well as other cilia-related diseases such as obesity.
登录
查看更多内容
影响因子：
64.5
作者：
BARGMANN, CI;HARTWIEG, E;HORVITZ, HR
通讯作者：
HORVITZ, HR
影响因子：
16.2
作者：
Fujiwara, M;Sengupta, P;McIntire, SL
通讯作者：
McIntire, SL
影响因子：
2.7
作者：
CASSADA, RC;RUSSELL, RL
通讯作者：
RUSSELL, RL
影响因子：
64.8
作者：
Ogg, S;Paradis, S;Ruvkun, G
通讯作者：
Ruvkun, G
影响因子：
4.4
作者：
Kitiratschky, Veronique B. D.;Wilke, Robert;Kohl, Susanne
通讯作者：
Kohl, Susanne