VLDL receptor regulates membrane progesterone receptor trafficking and non-genomic signaling

Abstract

Progesterone mediates its physiological functions through activation of both transcription-coupled nuclear receptors and 7-transmembrane progesterone receptors (mPRs) that transduce progesterone's rapid non-genomic actions by coupling to various signaling modules. However, the immediate mechanisms of action downstream of mPRs remain in question. Herein we use an untargeted quantitative proteomics approach to identify mPR interactors to better define progesterone non-genomic signaling. Surprisingly, we identify the VLDL Receptor (VLDLR) as an mPR partner required for its plasma membrane localization. Knocking down VLDLR abolishes non-genomic progesterone signaling, a phenotype that is rescued by overexpressing VLDLR. Mechanistically, we show that the VLDLR is required for mPR trafficking from the ER to the Golgi. Taken together, our data define a novel function for the VLDLR as a trafficking chaperone required for the mPR subcellular localization and as such non-genomic progesterone-dependent signaling.