A genome-wide dsRNA library screen for Drosophila genes that regulate the GBP/phospholipase C signaling axis that links inflammation to aging.

Objective: Invertebrates are productive models for understanding how inflammation, metabolism and aging are intertwined. We have deployed a dsRNA library screen to search for genes in Drosophila melanogaster-and hence identify human orthologs-that encode participants in a G-protein coupled, Ca-signaling pathway that regulates inflammation, metabolism and lifespan.

Results: We analyzed receptor-dependent, phospholipase C/Ca signaling responses to the growth-blocking peptide (GBP) cytokine in Drosophila S3 cells plated in 384-well plates containing dsRNAs that target approximately 14,000 Drosophila genes. We used Z-scores of < - 3 or > + 3 to define gene hits. Filtering of 'housekeeping' genes from these hits yielded a total of 82 and 61 Drosophila genes that either down-regulate or up-regulate Ca-signaling, respectively; representatives from these two groups were validated. Human orthologs of our hits may be modulators of Ca signaling in general, as well as being candidates for acting in molecular pathways that interconnect aging and inflammation.