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, Ca2+ -signaling pathway that regulates inflammation, metabolism and lifespan.

RESULTS: We analyzed receptor-dependent, phospholipase C/Ca2+ 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 Ca2+ -signaling, respectively; representatives from these two groups were validated. Human orthologs of our hits may be modulators of Ca2+ signaling in general, as well as being candidates for acting in molecular pathways that interconnect aging and inflammation.