Lysosomal degradation of ACVR1-Activin complexes negatively regulates signaling of Activins and Bone Morphogenetic Proteins

Abstract

AbstractBMP/TGFß family ligands have mainly been studied as factors that initiate Smad signaling. Activin A stands out as it initiates Smad2/3 signaling through ACVR1B, whereas it generates non-signaling complexes (NSCs) with ACVR1 which can inhibit ACVR1-mediated BMP signaling. In the genetic disorder fibrodysplasia ossificans progressiva (FOP), which is caused by missense mutations in ACVR1 (ACVR1.FOP), Activin•ACVR1.FOP•type II receptor complexes activate Smad1/5 signaling, mimicking those formed with BMPs. As the NSCs that Activin A forms with ACVR1 are stoichiometrically identical with the signaling complexes formed with ACVR1.FOP, we explored how NSCs differ from their signaling counterparts. We demonstrate that NSCs rapidly traffic to the lysosome and are degraded, thereby reducing Activin A levels, in addition to removing ACVR1 and associated type II receptors. Hence, Activin-ACVR1 NSCs negatively regulate both the availability of Activin A and the level of BMP signaling mediated by ACVR1. Hence, lysosomal trafficking and degradation of NSC is a novel regulatory mechanism of BMP/TGFß signaling whose physiological roles remain largely unexplored.