PT - JOURNAL ARTICLE AU - Varada Abhyankar AU - Bhagyashree Kaduskar AU - Siddhesh S. Kamat AU - Deepti Deobagkar AU - Girish Ratnaparkhi TI - <em>Drosophila</em> DNA/RNA methyltransferase contributes to robust host defense in ageing animals by regulating sphingolipid metabolism AID - 10.1101/362012 DP - 2018 Jan 01 TA - bioRxiv PG - 362012 4099 - http://biorxiv.org/content/early/2018/07/04/362012.short 4100 - http://biorxiv.org/content/early/2018/07/04/362012.full AB - Drosophila methyltransferase (Mt2) has been implicated in methylation of both DNA and tRNA. In this study, we demonstrate that loss of Mt2 activity leads to an age dependent decline of immune function in the adult fly. A newly eclosed adult has mild immune defects that exacerbate in a fifteen-day old Mt2−/− fly. The age dependent effects appear to be systemic, including disturbances in lipid metabolism, changes in cell shape of hemocytes and significant fold changes in levels of transcripts related to host defense. Lipid imbalance, as measured by quantitative lipidomics, correlates with immune dysfunction with high levels of immunomodulatory lipids, sphingosine-1phosphate (S1P) and ceramides, along with low levels of storage lipids. Activity assays on fly lysates confirm the age dependent increase in S1P and concomitant reduction of S1P lyase activity. We hypothesize that Mt2 functions to regulate genetic loci such as S1P lyase and this regulation is essential for robust host defense as the animal ages. Our study uncovers novel links between age dependent Mt2 function, innate immune response and lipid homeostasis.