The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate

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