Abstract
ABSTRACTUSP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia – crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 – a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling – as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains. Importantly, we show that both depletion and overexpression of catalytically active USP21 suppress Gli1-dependent transcription. Gli proteins are negatively regulated through protein kinase A (PKA)-dependent phosphorylation. We provide evidence that USP21 recruits and stabilises Gli1 at the centrosome where it promotes its phosphorylation by PKA. By revealing an intriguing functional pairing between a spatially restricted deubiquitylase and a kinase, our study highlights the centrosome as an important hub for signal coordination.
Highlights
Hedgehog (Hh) signaling plays an important role during development and has been implicated in diverse malignancies, including basal cell carcinomas, medullo- and glioblastoma, as well as pancreatic, colon and breast carcinomas (Amakye et al, 2013; Takebe et al, 2015)
WD-repeat-containing protein 47 (WDR47) colocalises with cytoplasmic microtubules through its interaction with microtubule-associated protein (MAP)8 (Wang et al, 2012a), whereas membrane protein palmitoylated 1 55 kDa (MPP1) has been localised to the basal body and the ciliary axoneme in murine photoreceptors (Gosens et al, 2007)
USP21CS itself presents as a doublet, a phenomenon commonly observed for catalytically inactive mutants of the USP family – e.g. USP4 and USP15 – which tend to accumulate as a mono- and polyubiquitylated species (Fig. 1D) (Hayes et al, 2012)
Summary
Hedgehog (Hh) signaling plays an important role during development and has been implicated in diverse malignancies, including basal cell carcinomas, medullo- and glioblastoma, as well as pancreatic, colon and breast carcinomas (Amakye et al, 2013; Takebe et al, 2015). Activation of the pathway is triggered by binding of Hh ligands to PTCH1 or PTCH2, which triggers their endocytosis and leads to de-repression of SMO, favouring activation of Ci/Gli proteins. These translocate into the nucleus and activate expression of Hh-responsive genes (Hui and Angers, 2011). It is the balance of active and repressive Gli proteins that determines signal strength and outcome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
