Rapid Progesterone signaling induces meiosis through a dual coreceptor trafficking trap

Abstract

Agonist-dependent signaling through plasma membrane (PM) receptors takes place through diverse modes, including post-translational modifications, second messengers, formation of signaling complexes, or ionic fluxes among others. Classical signaling downstream of steroid hormones engages nuclear/cytoplasmic receptors to induce transcription. Steroids further signal through a rapid mode within seconds to minutes independently of transcription. Despite the now well-recognized physiological roles of rapid progesterone (P4) signaling, the mechanistic steps remain poorly defined. Here we elucidate the early P4 rapid signaling steps that mediate the release of the oocyte meiotic arrest in the frog. P4 signals through two coreceptors mPR{beta}, which localizes at the PM; and ABHD2, which localizes intracellularly. Binding of P4 increases the interaction affinity between the two coreceptors leading to trapping of ABHD2 at the PM and activating signaling. Although P4 is not required for mPR{beta}-ABHD2 interaction at artificially high receptor concentration, it is essential under physiological conditions. We further show that ABHD2 is a dual pass transmembrane protein that binds P4 leading to intracellular PLA2 activity. Signaling through several receptor classes involves endocytosis, but the mPR{beta}-ABHD2 signaling modality is novel as it employs a PM trafficking trap to form the coreceptor complex and induce meiosis. Hence, our findings define a novel signaling modality for rapid steroid signaling.