WSB-1 is a Hedgehog-inducible ubiquitin ligase that modulates thyroid hormone activation and PTHrP secretion in the developing growth plate.

摘要

WSB-1 is a SOCS-box-containing WD-40 protein of unknown function that is induced by hedgehog signaling in embryonic structures during chicken development. Here we show that WSB-1 acts as an E3 ubiquitin ligase for the thyroid-hormone activating type 2 iodothyronine deiodinase (D2). The WD-40 propeller of WSB-1 recognizes a novel 18-amino acid loop in D2 that confers metabolic instability, while the SOCS-box domain mediates its interaction with an ubiquitinating catalytic core complex, modeled as Elongin BC-Cul5-Rbx1 (ECS^WSB-1). In the developing tibial growth plate, hedgehog-stimulated D2 ubiquitination via ECS^WSB-1 induces parathyroid hormone related peptide (PTHrP), thereby regulating chondrocyte differentiation. Thus, ECS^WSB-1 mediates a novel mechanism by which "systemic" thyroid hormone can effect local control of the hedgehog-PTHrP negative feedback loop and thus skeletogenesis.