Control of secreted protein gene expression and the mammalian secretome by the metabolic regulator PGC-1a. Mus musculus

Secreted proteins serve pivotal roles in the development of multicellular organisms, acting as structural matrix, extracellular enzymes and signal molecules. In this study we demonstrate, unexpectedly, that PGC-1α, a critical transcriptional co-activator of metabolic gene expression, functions to down-regulate expression of diverse genes encoding secreted molecules and extracellular matrix (ECM) components to modulate the secretome. We show that both endogenous and exogenous PGC-1α down-regulate expression of numerous genes encoding secreted molecules. Mechanistically, results obtained using mRNA stability measurements as well as intronic RNA expression analysis are consistent with a transcriptional effect of PGC-1α on expression of genes encoding secreted proteins. Interestingly, PGC-1α requires the central heat shock response regulator HSF1 to affect some of its targets, and both factors co-reside on several target genes encoding secreted molecules in cells. Finally, using a mass spectrometric analysis of secreted proteins, we demonstrate that PGC-1α modulates the secretome of mouse embryonic fibroblasts (MEFs). Overall design: Cells were grown in 12-well plates and control adenoviruses (Ad-control) or PGC-1alpha (Ad-PGC-1α) encoding adenoviruses were directly added to the culture medium where indicated. PGC-1α KO and PGC-1α WT differentiated brown adipocytes were examined.