Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Paola Infante, Roberta Faedda, Flavia Bernardi, Francesca Bufalieri, Ludovica Lospinoso Severini, Romina Alfonsi, Daniela Mazzà, Mariangela Siler, Sonia Coni, Agnese Po, Marialaura Petroni, Elisabetta Ferretti, Mattia Mori, Enrico De Smaele, Gianluca Canettieri, Carlo Capalbo, Marella Maroder, Isabella Screpanti, Marcel Kool, Stefan M. Pfister, Daniele Guardavaccaro, Alberto Gulino and Lucia Di Marcotullio ()
Additional contact information
Paola Infante: Istituto Italiano di Tecnologia
Roberta Faedda: University La Sapienza
Flavia Bernardi: University La Sapienza
Francesca Bufalieri: University La Sapienza
Ludovica Lospinoso Severini: University La Sapienza
Romina Alfonsi: University La Sapienza
Daniela Mazzà: University La Sapienza
Mariangela Siler: University La Sapienza
Sonia Coni: University La Sapienza
Agnese Po: University La Sapienza
Marialaura Petroni: Istituto Italiano di Tecnologia
Elisabetta Ferretti: University La Sapienza
Mattia Mori: Istituto Italiano di Tecnologia
Enrico De Smaele: University La Sapienza
Gianluca Canettieri: University La Sapienza
Carlo Capalbo: University La Sapienza
Marella Maroder: University La Sapienza
Isabella Screpanti: University La Sapienza
Marcel Kool: Hopp Children’s Cancer Center at the NCT (KiTZ)
Stefan M. Pfister: Hopp Children’s Cancer Center at the NCT (KiTZ)
Daniele Guardavaccaro: Hubrecht Institute-KNAW and University Medical Center Utrecht
Alberto Gulino: University La Sapienza
Lucia Di Marcotullio: University La Sapienza

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis.

Date: 2018
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DOI: 10.1038/s41467-018-03339-0

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