DrosophilaDNA/RNA methyltransferase contributes to robust host defense in ageing animals by regulating sphingolipid metabolism

Abstract

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.

Genome-wide comparison of DNA methylation between life cycle stages ofDrosophila melanogasterusing high-throughput sequencing techniques

“…Hence, it can be postulated that a novel methyltransferase might be working closely with Dnmt2 to establish the methylation pattern observed in wild-type flies. Dnmt2 mutant flies were shown to be susceptible temperature, oxidative and viral stress 16,17,29 ; additionally, the ability to handle bacterial infection in these flies is reported to reduce in an age dependent manner accompanied by changes in hemocyte shape and lipid profile 18 . In the light of the presented data, further analysis of the DNA methylation in the adult Dnmt2 mutant flies might reveal its role in handling biotic or abiotic stress.…”

“…The dDNMT2 gene has been implied to be involved in the regulation of stress and immune response 15–17 . Involvement of Mt2 in contributing to Drosophila immunity against bacterial infection in an age-dependent manner accompanied by changes in the sphingolipid metabolism has been demonstrated 18 . The embryos of DNMT2 knockout flies have shown the persistence of DNA methylation albeit with an altered pattern clearly indicating a possibility of existence an unknown DNA methyltransferase in Drosophila 5 .…”

Paternal knockdown of tRNA (cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red flour beetles

“…During the stress response, Dnmt2 appears to control the fragmentation of tRNA and can be located at cellular stress compartments 15,51 . More recently, it has also been demonstrated that the knockout of Dnmt2 leads to a decline of immune function with ageing in adult flies 52 . Finally, its absence disrupts the small interfering RNA pathway by inhibiting dsRNA degradation by Dicer 51 .…”

The tRNA‐associated dysregulation in immune responses and immune diseases

“…Compared to wild-type rats, Hcy-stimulated NSun2(-/-) rats showed significantly reduced levels of ICAM-1 and leucocyte adhesion to endothelial cells. 76 Specifically, Dnmt2(-/-) flies presented an age-dependent decrease in sphingosine-1-phosphate (S1P) lyase activity and concomitant accumulation of S1P, which in turn led to age-dependent damage to anti-infective capacity. Analogously, NSun2 methylated the IL-17A mRNA in an m5C pattern to promote the translation of IL-17A in T lymphocytes, thereby mediating the chronic inflammation caused by plasma Hcy.…”

“…75 New studies confirmed that defects in Drosophila Dnmt2 reduced immune function with age by affecting sphingolipid metabolism. 76 Specifically, Dnmt2(-/-) flies presented an age-dependent decrease in sphingosine-1-phosphate (S1P) lyase activity and concomitant accumulation of S1P, which in turn led to age-dependent damage to anti-infective capacity. Mechanistically, Dnmt2 might regulate the genetic loci of S1P lyase, so that ageing animals still had a strong host defence against pathogens.…”