Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress
Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress
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DOI：
10.1073/pnas.1712453115
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发表时间：
2017-12-26
影响因子：
11.1
通讯作者：
Hayakawa, Yoichi
中科院分区：
文献类型：
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作者：
Sung, Eui Jae;Ryuda, Masasuke;Hayakawa, Yoichi
从系统层面理解尼古丁介导的组织间信号传导是深入了解衰老和炎症之间联系的关键之一。在这里，我们采用果蝇，在高等动物中的细胞因子信号通路分析的常规模型，以确定受体的生长阻断肽（GBP）细胞因子。先前已经确定磷脂酶C/Ca 2+信号通路介导对GBP的先天免疫应答，我们进行了dsRNA文库筛选，以寻找调节果蝇S3细胞中Ca 2+动员的基因。迄今为止的孤儿G蛋白偶联受体，玛士撒拉样受体-10（Mthl 10），是一个重大的打击。二次筛选证实了荧光团标记的GBP与S3细胞和重组MthllO-胞外域的特异性结合。我们发现GBP的代谢、免疫和应激保护作用都通过Mthl 10相互联系。这是我们在三种果蝇模型系统中通过MthllO敲低建立的：在血细胞样果蝇S2细胞中，MthllO敲低降低了GBP介导的先天免疫应答;在幼虫中，MthllO敲低降低了响应于低温的抗微生物肽的表达;在成年果蝇中，MthllO敲低增加了感染藤黄微球菌后的死亡率，并降低了GBP介导的胰岛素样肽的分泌。我们进一步报道，生物体适应性为利用Mthl 10整合GBP的所有这些各种稳态属性付出了代价：我们发现GBP表达升高会缩短寿命。相反，MthllO敲低延长寿命。我们描述了我们的数据如何提供机会，进一步分子讯问阴阳之间的稳态和长寿。
A systems-level understanding of cytokine-mediated, intertissue signaling is one of the keys to developing fundamental insight into the links between aging and inflammation. Here, we employed Drosophila, a routine model for analysis of cytokine signaling pathways in higher animals, to identify a receptor for the growth-blocking peptide (GBP) cytokine. Having previously established that the phospholipase C/Ca2+ signaling pathway mediates innate immune responses to GBP, we conducted a dsRNA library screen for genes that modulate Ca2+ mobilization in Drosophila S3 cells. A hitherto orphan G protein coupled receptor, Methuselah-like receptor-10 (Mthl10), was a significant hit. Secondary screening confirmed specific binding of fluorophore-tagged GBP to both S3 cells and recombinant Mthl10-ectodomain. We discovered that the metabolic, immunological, and stress-protecting roles of GBP all interconnect through Mthl10. This we established by Mthl10 knockdown in three fly model systems: in hemocyte-like Drosophila S2 cells, Mthl10 knockdown decreases GBP-mediated innate immune responses; in larvae, Mthl10 knockdown decreases expression of antimicrobial peptides in response to low temperature; in adult flies, Mthl10 knockdown increases mortality rate following infection with Micrococcus luteus and reduces GBP-mediated secretion of insulin-like peptides. We further report that organismal fitness pays a price for the utilization of Mthl10 to integrate all of these various homeostatic attributes of GBP: We found that elevated GBP expression reduces lifespan. Conversely, Mthl10 knockdown extended lifespan. We describe how our data offer opportunities for further molecular interrogation of yin and yang between homeostasis and longevity.