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; Lucia Di Marcotullio

doi:10.1038/s41467-018-03339-0

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 PfisterDaniele Guardavaccaro, Alberto Gulino, Lucia Di Marcotullio

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

50 Citations (Scopus)

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.

Original language	English
Pages (from-to)	976
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03339-0
Publication status	Published - 07 Mar 2018

Keywords

Amino Acid Motifs
Animals
Carcinogenesis
Female
Hedgehog Proteins/genetics
Humans
Medulloblastoma/enzymology
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Repressor Proteins/chemistry
Signal Transduction
Ubiquitin-Protein Ligases/genetics
Ubiquitination
beta-Arrestin 2/genetics

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10.1038/s41467-018-03339-0

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Infante, P., Faedda, R., Bernardi, F., Bufalieri, F., Lospinoso Severini, L., Alfonsi, R., Mazzà, D., Siler, M., Coni, S., Po, A., Petroni, M., Ferretti, E., Mori, M., De Smaele, E., Canettieri, G., Capalbo, C., Maroder, M., Screpanti, I., Kool, M., ... Di Marcotullio, L. (2018). Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis. Nature Communications, 9(1), 976. https://doi.org/10.1038/s41467-018-03339-0

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

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.",

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author = "Paola Infante and Roberta Faedda and Flavia Bernardi and Francesca Bufalieri and {Lospinoso Severini}, Ludovica and Romina Alfonsi and Daniela Mazz{\`a} and Mariangela Siler and Sonia Coni and Agnese Po and Marialaura Petroni and Elisabetta Ferretti and Mattia Mori and {De Smaele}, Enrico and Gianluca Canettieri and Carlo Capalbo and Marella Maroder and Isabella Screpanti and Marcel Kool and Pfister, {Stefan M} and Daniele Guardavaccaro and Alberto Gulino and {Di Marcotullio}, Lucia",

year = "2018",

month = mar,

day = "7",

doi = "10.1038/s41467-018-03339-0",

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Infante, P, Faedda, R, Bernardi, F, Bufalieri, F, Lospinoso Severini, L, Alfonsi, R, Mazzà, D, Siler, M, Coni, S, Po, A, Petroni, M, Ferretti, E, Mori, M, De Smaele, E, Canettieri, G, Capalbo, C, Maroder, M, Screpanti, I, Kool, M, Pfister, SM, Guardavaccaro, D, Gulino, A & Di Marcotullio, L 2018, 'Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis', Nature Communications, vol. 9, no. 1, pp. 976. https://doi.org/10.1038/s41467-018-03339-0

TY - JOUR

T1 - Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

AU - Infante, Paola

AU - Faedda, Roberta

AU - Bernardi, Flavia

AU - Bufalieri, Francesca

AU - Lospinoso Severini, Ludovica

AU - Alfonsi, Romina

AU - Mazzà, Daniela

AU - Siler, Mariangela

AU - Coni, Sonia

AU - Po, Agnese

AU - Petroni, Marialaura

AU - Ferretti, Elisabetta

AU - Mori, Mattia

AU - De Smaele, Enrico

AU - Canettieri, Gianluca

AU - Capalbo, Carlo

AU - Maroder, Marella

AU - Screpanti, Isabella

AU - Kool, Marcel

AU - Pfister, Stefan M

AU - Guardavaccaro, Daniele

AU - Gulino, Alberto

AU - Di Marcotullio, Lucia

PY - 2018/3/7

Y1 - 2018/3/7

N2 - 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.

AB - 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.

KW - Amino Acid Motifs

KW - Animals

KW - Carcinogenesis

KW - Female

KW - Hedgehog Proteins/genetics

KW - Humans

KW - Medulloblastoma/enzymology

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred NOD

KW - Mice, Knockout

KW - Mice, SCID

KW - Repressor Proteins/chemistry

KW - Signal Transduction

KW - Ubiquitin-Protein Ligases/genetics

KW - Ubiquitination

KW - beta-Arrestin 2/genetics

U2 - 10.1038/s41467-018-03339-0

DO - 10.1038/s41467-018-03339-0

M3 - Article

C2 - 29515120

SN - 2041-1723

VL - 9

SP - 976

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Keywords

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