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.

The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability / Heride, Claire; Rigden, Daniel J.; Bertsoulaki, Erithelgi; Cucchi, Danilo; DE SMAELE, Enrico; Clague, Michael J.; Urbé, Sylvie. - In: JOURNAL OF CELL SCIENCE. - ISSN 0021-9533. - STAMPA. - 129:(2016), pp. 4001-4013. [10.1242/jcs.188516]

The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability

CUCCHI, DANILO;DE SMAELE, Enrico;
2016

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.
2016
Ubiquitin Hedgehog Gli1 PKA Phosphorylation DUB
01 Pubblicazione su rivista::01a Articolo in rivista
The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability / Heride, Claire; Rigden, Daniel J.; Bertsoulaki, Erithelgi; Cucchi, Danilo; DE SMAELE, Enrico; Clague, Michael J.; Urbé, Sylvie. - In: JOURNAL OF CELL SCIENCE. - ISSN 0021-9533. - STAMPA. - 129:(2016), pp. 4001-4013. [10.1242/jcs.188516]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/903195
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