Mef2 in Sickness and in Health Infection Can Cause Weight Loss, but Genes and Metabolic Activities

RESEARCH HIGHLIGHTS

Nature Reviews Immunology | AOP, published online 25 October 2013; doi:10.1038/nri3563

IMMUNOMETABOLISM Mef2 in sickness and in health Infection can cause weight loss, but genes and metabolic activities. In the required for the induction of AMP the link between infection-induced functional RNAi screens, Mef2 was expression in vivo using flies express- immune activation and loss of one of five genes that were required ing wild-type or mutant reporter anabolic function is poorly under- for D. melanogaster survival following constructs. Further experiments stood. Now, researchers studying Mycobacterium marinum infection. indicated that Mef2 and Tbp form infection in Drosophila melanogaster Moreover, flies with a targeted a complex on the Mef2–TATA box- have found that the transcription knockdown of Mef2 expression in the binding sites of numerous AMPs, as factor Mef2 (myocyte-specific fat body (which is equivalent to the well as of other immune genes, and Mef2 … enhancer factor 2) controls a switch mammalian liver and adipose tissue) that this is required for the normal controls a from metabolic gene expression to showed increased susceptibility to transcriptional induction of these switch from immune-response gene expression infection with several other micro- genes. during infection in flies. organisms (Listeria monocytogenes, Microarray data also showed that metabolic gene Clark et al. used gene expression Enterobacter cloacae and Candida when the expression of antimicrobial expression microarrays and D. melanogaster with albicans), which target the Toll or Imd genes was induced, the expression of to immune- targeted protein deficiencies (using pathways. metabolic genes was reduced. How RNA interference (RNAi)) to identify Further analysis of the microar- is this counter-regulation achieved? response gene the pathways and the transcriptional ray data revealed that a cluster of Mef2 was found to be phosphoryl- expression networks that regulate the response to genes predicted to be targeted by ated on a conserved region of its during infection. By clustering the genes that Mef2 contained metabolic enzymes DNA-binding domain in healthy infection were co-regulated and that shared that were rapidly and transiently D. melanogaster but this phospho- transcription factor-binding sites, the downregulated 3–6 hours after infec- rylation was lost following infection. in flies authors identified Mef2 as a potential tion. Similarly, the expression of a Experiments using flies expressing regulator of both immune response group of enzymes that are involved wild-type non-phosphorylatable in glycogenesis and lipogenesis Mef2 or a constitutively phosphoryl- was lower in Mef2-knockdown ated form of Mef2 showed that only D. melanogaster than in control flies, unphosphorylated forms of Mef2 and Mef2-knockdown flies died associate with Tbp. So, the loss of more rapidly when starved. This Mef2 phosphorylation that occurs suggests that a metabolic defect in following infection facilitates the for- Mef2-knockdown flies contributes to mation of the Mef2–Tbp complexes their poor survival after infection by that are responsible for the induction decreasing their ability to withstand of AMP expression. Consistent infection-induced weight loss. with the idea that phosphorylation In addition to this metabolic switches Mef2 target gene reper- defect, Mef2-knockdown D. mela- toires, only the phosphorylatable nogaster showed a marked reduction forms of Mef2 promoted expression in their expression of various antimi- of metabolic genes. crobial peptides (AMPs) in response So, in flies, phosphorylation of to infection. Analysis of putative Mef2 controls a switch between regulatory regions from AMP genes ensuring storage of fat and glycogen consistently revealed the presence and mounting a protective response of a predicted Mef2-binding site to infection. that overlapped with a TATA box Lucy Bird (which is bound by TATA-binding ORIGINAL RESEARCH PAPER Clark, R. I. et al. protein (Tbp)). This Mef2–TATA MEF2 is an in vivo immune-metabolic switch. Cell

GETTY 155, 435–447 (2013) box-binding site was shown to be

NATURE REVIEWS | IMMUNOLOGY VOLUME 13 | DECEMBER 2013