The centrosomal Deubiquitylase USP21 regulates Gli1 transcriptional activity and stability

Heride, C, Rigden, DJ ORCID: 0000-0002-7565-8937, Bertsoulaki, E, Cucchi, D, De Smaele, E, Clague, MJ ORCID: 0000-0003-3355-9479 and Urbe, S ORCID: 0000-0003-4735-9814 (2016) The centrosomal Deubiquitylase USP21 regulates Gli1 transcriptional activity and stability. Journal of Cell Science, 129 (21). pp. 4001-4013.

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Abstract

USP21 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.

Item Type:	Article
Uncontrolled Keywords:	Ubiquitin, Hedgehog, Gli1, PKA, Phosphorylation, DUB
Depositing User:	Symplectic Admin
Date Deposited:	12 Sep 2016 10:41
Last Modified:	19 Jan 2023 07:30
DOI:	10.1242/jcs.188516
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3003235