Arc1 and the microbiota together modulate growth and metabolic traits in Drosophila

Abstract

Perturbations to animal-associated microbial communities (the microbiota) have deleterious effects on various aspects of host fitness, but the molecular processes underlying these impacts are poorly understood. Here we identify a novel connection between the microbiota and the neuronal factor Arc1 that affects growth and metabolism in Drosophila. We find that Arc1 exhibits tissue-specific microbiota-dependent expression changes, and that germ-free flies bearing a null mutation of Arc1 exhibit delayed and stunted larval growth, along with a variety of molecular, cellular, and organismal traits indicative of metabolic dysregulation. Remarkably, we show that the majority of these phenotypes can be fully suppressed by mono-association with a single Acetobacter sp. isolate, through mechanisms involving both bacterial diet modification and live bacteria. Additionally, we provide evidence that Arc1 function in key neuroendocrine cells of the larval brain modulates growth and metabolic homeostasis under germ-free conditions. Our results reveal a novel role for Arc1 in modulating physiological responses to the microbial environment, and highlight how host-microbe interactions can profoundly impact the phenotypic consequences of genetic mutations in an animal host.

The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging

“…5F). These proteins include Arc1 and Arc2 (activity-regulated cytoskeleton-associated protein 1 and 2), which regulate starvation-induced locomotion, the neuromuscular junction, and metabolism (58)(59)(60); the glycine N-methyltransferase Gnmt enzyme, which generates sarcosine and controls the amount of the methyl donor S-adenosylmethionine (61,62); and CG4594, which encodes for an enzyme involved in fatty acid beta oxidation. In addition to rescuing protein changes induced by eff RNAi, overexpression of hUBE2D2 by itself reduced the levels of Arc1, Arc2, Gnmt, and CG4594.…”

Steroid hormone regulation of innate immunity in Drosophila melanogaster

“…In fly larvae, which dwell in and continually feed on the microbe-rich food substrate, the gut microbiota are a critical determinant of growth rate and growth capacity. Transcript levels of the 20E biosynthetic enzymes shroud and shade [ 110 ] and the early gene Eip74B [ 111 ] have been reported to decrease in germ-free larvae, suggesting interactions with the gut microbiota can affect expression of certain 20E-related genes during development. At pupariation, Nunes and colleagues [ 40 ] found that 20E-EcR function in the larval gut (similarly to the fat body) up-regulates multiple AMPs, thereby protecting against excess microbiota loads in late pupae.…”

An extracellular vesicle targeting ligand that binds to Arc proteins and facilitates Arc transport in vivo

“…The dArc2 gene, which encodes a truncated protein, was likely generated by a gene duplication, and the dArc1 and dArc2 genes are adjacent(Mattaliano et al, 2007). dArc1 functions in larval and adult brain neurons to regulate aspects of metabolism(Keith et al, 2021; Mattaliano et al ., 2007; Mosher et al, 2015). Arc and dArc1 evolved independently from retrotransposon Gag proteins(Shepherd, 2018).…”