Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru, India.
PLoS Genet. 2023 Sep 21;19(9):e1010962. doi: 10.1371/journal.pgen.1010962. eCollection 2023 Sep.
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.
进化上保守的基因通常在生物机体生理学中发挥关键作用。在这里，我们描述了一个以前未被表征的 III 类金属磷酸二酯酶在果蝇中的多种作用，该酶是在哺乳动物大脑中表达的 MPPED1 和 MPPED2 蛋白的同源物。dMpped 是 CG16717 的产物，以金属依赖的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。对 dMppedKO 果蝇的 RNA-seq 分析显示先天免疫途径的失调。dMppedKO 果蝇的寿命缩短，这可以在 Dredd 低等位基因中得到恢复，表明抗菌肽的过度产生导致寿命缩短。在 dMppedKO 果蝇的大脑中，cAMP 和 cGMP 的水平升高，在神经元表达 dMpped 后得到恢复，抗菌肽的水平降低，正常寿命得到恢复。我们观察到 dMpped 在果蝇大脑的触角叶中表达。dMppedKO 果蝇表现出特定引诱剂感知和干燥敏感性缺陷，与敲除果蝇中 Obp28 和 Obp59 的过表达相关。重要的是，哺乳动物 MPPED2 的神经元表达在 dMppedKO 果蝇中恢复了寿命。这是第一个描述进化上保守的金属磷酸二酯酶的多效性作用的描述，该酶可能在生物体内的不同信号通路中兼职发挥作用。
