Crossregulation of Insulin signalling and innate immunity

Abstract

Insulin signalling (IlS) is a major signalling cascade, which is conserved from worm to human. Beside the regulation of blood sugar levels, different other processes like organismal growth, body size, ageing or autophagy are directly controlled or at least influenced by IlS. This work identifies a novel and essential component of IlS in the fruit fly Drosophila melanogaster, which is the Steppke protein, the homologue of the vertebrate Cytohesin family of proteins. Steppke mutant animals are reduced in size and show severe growth defects. Steppke functions downstream of the Insulin Receptor and upstream of PI3K. In consequence, steppke mutant animals show typical phenotypes like reduced AKT/PKB phosphorylation, enhanced FOXO nuclear localization or misexpression of FOXO target genes. Moreover, the expression of antimicrobial peptides (AMPs), a class of immune effector genes, is enhanced in steppke mutants. This does not represent a steppke specific phenotype, but is the consequence of reduced IlS activity in the mutant animals. AMP expression is shown to depend on nutrition and to be directly regulated by FOXO, the main transcription factor downstream of IlS. FOXO directly binds to the regulatory regions of AMPs, thereby driving their expression, which establishes a novel link between IlS and innate immunity in the fly. Experiments in human culture cell lines indicate that a FOXO dependent mechanism of AMP regulation is also conserved in vertebrates.