Evolutionarily conserved genes often play critical roles in organismal physiology. Here, we describe multiple roles of a previously uncharacterized Class III metallophosphodiesterase in Drosophila, an ortholog of the MPPED1 and MPPED2 proteins expressed in the mammalian brain. dMpped, the product of CG16717, hydrolyzed phosphodiester substrates including cAMP and cGMP in a metal-dependent manner. dMpped is expressed during development and in the adult fly. RNA-seq analysis of dMppedKO flies revealed misregulation of innate immune pathways. dMppedKO flies showed a reduced lifespan, which could be restored in Dredd hypomorphs, indicating that excessive production of antimicrobial peptides contributed to reduced longevity. Elevated levels of cAMP and cGMP in the brain of dMppedKO flies was restored on neuronal expression of dMpped, with a concomitant reduction in levels of antimicrobial peptides and restoration of normal life span. We observed that dMpped is expressed in the antennal lobe in the fly brain. dMppedKO flies showed defective specific attractant perception and desiccation sensitivity, correlated with the overexpression of Obp28 and Obp59 in knock-out flies. Importantly, neuronal expression of mammalian MPPED2 restored lifespan in dMppedKO flies. This is the first description of the pleiotropic roles of an evolutionarily conserved metallophosphodiesterase that may moonlight in diverse signaling pathways in an organism.

中文翻译：

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果蝇中进化上保守的金属磷酸二酯酶的神经元表达揭示了在长寿和气味反应中的多效性作用。

进化保守的基因通常在生物体生理学中发挥关键作用。在这里，我们描述了果蝇中先前未表征的 III 类金属磷酸二酯酶的多种作用，该酶是哺乳动物大脑中表达的 MPPED1 和 MPPED2 蛋白的直系同源物。dMpped 是 CG16717 的产物，以金属依赖性方式水解磷酸二酯底物，包括 cAMP 和 cGMP。dMpped 在发育过程中和成年果蝇中表达。dMppedKO 果蝇的 RNA-seq 分析揭示了先天免疫途径的错误调节。dMppedKO 果蝇的寿命缩短，但在 Dredd 亚型体中可以恢复，这表明抗菌肽的过量产生导致寿命缩短。dMppedKO 果蝇大脑中 cAMP 和 cGMP 水平升高，在 dMpped 神经元表达后恢复，同时抗菌肽水平降低并恢复正常寿命。我们观察到 dMpped 在果蝇大脑的触角叶中表达。dMppedKO 果蝇表现出有缺陷的特异性引诱剂感知和干燥敏感性，与敲除果蝇中 Obp28 和 Obp59 的过度表达相关。重要的是，哺乳动物 MPPED2 的神经元表达恢复了 dMppedKO 果蝇的寿命。这是对进化上保守的金属磷酸二酯酶的多效性作用的首次描述，该酶可能兼职于生物体的多种信号传导途径中。