Caenorhabditis elegans junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin.

IF 3.3 3区生物学 Genetics Pub Date : 2021-08-09 DOI:10.1093/genetics/iyab063

Christopher A Piggott, Zilu Wu, Stephen Nurrish, Suhong Xu, Joshua M Kaplan, Andrew D Chisholm, Yishi Jin

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Abstract

The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole Caenorhabditis elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 colocalizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68 RyR calcium channel, and is required for animal movement. In neurons, JPH-1 colocalizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in the soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell nonautonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and with unc-68 for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68 is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

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秀丽隐杆线虫嗜结膜蛋白具有组织特异性功能，并通过突触延伸蛋白调节神经传递。

嗜junctophilin蛋白家族将质膜（PM）和内质网（ER）膜连接在一起，并耦合PM和ER定位的钙通道。了解嗜junctophilins的体内功能对于解剖ER-PM接触位点的生理作用具有重要意义。在这里，我们发现唯一的秀丽隐杆线虫嗜junctophilin JPH-1定位于神经元和肌肉中的离散膜接触位点，并具有重要的组织特异性功能。jph-1无效突变体由于咽肌收缩较弱，导致进食减少，生长发育缓慢。在体壁肌肉中，JPH-1与PM定位的EGL-19电压门控钙通道和ER定位的UNC-68 RyR钙通道共定位，是动物运动所必需的。在神经元中，JPH-1与胞体中的膜接触位点蛋白Extended SYnaptoTagmin 2（ESYT-2）共定位，并存在于突触前释放位点附近。有趣的是，jph-1和esyt-2无效突变体在对涕灭威的反应中表现出相互抑制，这表明jph-1和esyt-2在神经肌肉突触传递中具有拮抗作用。此外，我们发现jph-1在损伤后轴突再生中具有意想不到的细胞非自主作用。遗传双突变体分析表明，jph-1与两个PM定位的电压门控钙通道egl-19和unc-2以及unc-68在动物健康和发育方面的作用途径重叠。最后，我们发现jph-1调节EGL-19和UNC-68的共定位，并且UNC-68是jph-1定位到ER-PM点所必需的。我们的数据证明了亲junctophilin在细胞生理学中的重要作用，也为亲Junctolhilin如何与体内其他钙通道一起发挥作用提供了见解。

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来源期刊

Genetics 生物-遗传学

CiteScore

6.20

自引率

6.10%

发文量

177

期刊介绍： GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.