2013年6月25日,，北京生命科學(xué)研究董夢(mèng)秋實(shí)驗(yàn)室在《eLIFE》雜志發(fā)表題為“CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16”的文章,。
本文研究發(fā)現(xiàn)，除了經(jīng)典的胰島素信號(hào)傳導(dǎo)通路,，鈣離子／鈣調(diào)素依賴性蛋白激酶II（CAMKII）和蛋白磷酸酶Calcineurin也參與調(diào)控秀麗線蟲的壽命,，并且也通過FOXO家族轉(zhuǎn)錄因子DAF-16起作用。雖然CAMKII和胰島素信號(hào)通路中的AKT-1,、AKT-2激酶都直接磷酸化DAF-16,，但它們的磷酸化位點(diǎn)不同、引起的效應(yīng)截然相反,。AKT-1和AKT-2介導(dǎo)的磷酸化抑制DAF-16,，使其滯留在細(xì)胞質(zhì)中，不能進(jìn)入細(xì)胞核啟動(dòng)“延年益壽”的基因表達(dá)程序,。CAMKII磷酸化DAF-16第286位的絲氨酸 (S286),，促進(jìn)DAF-16在細(xì)胞核內(nèi)的定位、增強(qiáng)DAF-16的轉(zhuǎn)錄活性,。Calcineurin則與CAMKII相拮抗,，特異性去除S286的磷酸化修飾。所以,，CAMKII持續(xù)激活的突變體線蟲,、胰島素信號(hào)通路部分失活（導(dǎo)致AKT激酶活性降低）的突變體和Calcineurin缺失的突變體都比野生型長壽。此外,，CAMKII介導(dǎo)了包括饑餓,、熱脅迫以及氧化脅迫在內(nèi)的一系列環(huán)境因素對(duì)DAF-16的調(diào)控。CAMKII和Calcineurin通過響應(yīng)外部信號(hào)來調(diào)整DAF-16轉(zhuǎn)錄活性的方式是對(duì)胰島素信號(hào)通路內(nèi)分泌調(diào)節(jié)機(jī)制的補(bǔ)充,。兩者相互協(xié)調(diào),，以胰島素信號(hào)為主，CAMKII和Calcineurin為輔,，通過DAF-16整合信號(hào),，共同調(diào)節(jié)線蟲的壽命。
作者還發(fā)現(xiàn)CAMKII和Calcineurin對(duì)FOXO的調(diào)控機(jī)制在進(jìn)化上高度保守,。在哺乳動(dòng)物細(xì)胞中,，CAMKIIA和Calcineurin通過FOXO3的特定位點(diǎn)（小鼠FOXO3第298位的絲氨酸，對(duì)應(yīng)于DAF-16的S286位點(diǎn)）的磷酸化和去磷酸化來調(diào)節(jié)FOXO3的轉(zhuǎn)錄活性,。糖尿病和其它一些衰老相關(guān)的疾病的發(fā)生可能與CAMKII和Calcineurin對(duì)FOXO3的調(diào)控失常有關(guān),。
該項(xiàng)研究由我所董夢(mèng)秋實(shí)驗(yàn)室與中科院生物物理所袁增強(qiáng)實(shí)驗(yàn)室合作完成，兩位PI為通訊作者,。文章第一作者是我所博士研究生陶莉,，第二作者是生物物理所博士研究生謝琦。董夢(mèng)秋實(shí)驗(yàn)室的丁曰和,、李尚桐,、張艷萍、譚丹以及袁增強(qiáng)實(shí)驗(yàn)室的彭聲飴也參與了本文的研究工作,。感謝科技部,、基金委和北京市的資助。（生物谷Bioon.com）
doi:10.7554/eLife.00518.001
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CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16
Tao L, Xie Q, Ding YH, Li ST, Peng S, Zhang YP, Tan D, Yuan Z, Dong MQ.
The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin (PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6•CNB-1 and UNC-43, the C. elegans Calcineurin and Ca(2+)/calmodulin-dependent kinase type II (CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC-43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6•CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin.
