A proteomic atlas of insulin signaling reveals tissue-specific mechanisms of longevity-assurance

ABSTRACT: Lowered activity of the insulin/IGF signaling (IIS) network can ameliorate the effects of ageing in model organisms and, possibly, humans. Remodelling of the RNA transcriptome of long-lived IIS mutants has been extensively documented, but is only weakly predictive of consequent changes in protein expression, and the causal mechanisms at work, particularly in specific tissues, remain unclear. We have characterised changes in the proteomes of four key insulin-sensitive tissues of a long-lived Drosophila IIS mutant. We identified with high confidence ~6000 proteins, constituting 44% of the predicted proteome, which were mainly tissue-specific in expression. Lowered IIS resulted in robust, highly reproducible and tissue-specific responses, particularly pronounced in the brain and intestine, 60% of which were not detected in previous profiles of changes in RNA expression. Lowered IIS resulted in reduced expression of ribosome-associated proteins in the fat body, and a corresponding, tissue-specific reduction in translation. Mitochondrial electron transport chain proteins were increased in the fat body, leading to increased respiration, and the increase was both necessary for IIS-mediated lifespan extension and sufficient alone to mediate it. Proteosomal subunits were differentially regulated in IIS mutant gut, and directed expression of a single proteosomal subunit, RPN6, in the gut was sufficient to increase assembly and activity of the proteasome and to extend lifespan. Inhibition of proteasome activity specifically abolished IIS-mediated longevity. Tissue-specific proteomic profiling has thus deconstructed the diverse responses to reduced IIS, and demonstrated that they act in concert to ameliorate ageing.

INSTRUMENT(S):

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

SUBMITTER: Robert Sehlke  

LAB HEAD: Linda Partridge

PROVIDER: PXD006225 | Pride | 2017-09-13

REPOSITORIES: Pride