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The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis

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  • Elena Rivkin

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

  • Stephanie M. Almeida

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

  • Derek F. Ceccarelli

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada)

  • Yu-Chi Juang

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada)

  • Teresa A. MacLean

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

  • Tharan Srikumar

    (University of Toronto and Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada)

  • Hao Huang

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada)

  • Wade H. Dunham

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

  • Ryutaro Fukumura

    (Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan)

  • Gang Xie

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada)

  • Yoichi Gondo

    (Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan)

  • Brian Raught

    (University of Toronto and Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada)

  • Anne-Claude Gingras

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

  • Frank Sicheri

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

  • Sabine P. Cordes

    (Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, 1 King’s Crescent, Toronto, Ontario M5S 1A8, Canada)

Abstract

A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-κB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.

Suggested Citation

  • Elena Rivkin & Stephanie M. Almeida & Derek F. Ceccarelli & Yu-Chi Juang & Teresa A. MacLean & Tharan Srikumar & Hao Huang & Wade H. Dunham & Ryutaro Fukumura & Gang Xie & Yoichi Gondo & Brian Raught , 2013. "The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis," Nature, Nature, vol. 498(7454), pages 318-324, June.
    • Handle: RePEc:nat:nature:v:498:y:2013:i:7454:d:10.1038_nature12296
    DOI: 10.1038/nature12296
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    Cited by:

    1. Hannah Schünke & Ulrike Göbel & Ivan Dikic & Manolis Pasparakis, 2021. "OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Yi Luan & Wenying Long & Lisi Dai & Panfeng Tao & Zhifen Deng & Zongping Xia, 2024. "Linear ubiquitination regulates the KSHV replication and transcription activator protein to control infection," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Esther Hoste & Kim Lecomte & Karl Annusver & Niels Vandamme & Jana Roels & Sophia Maschalidi & Lien Verboom & Hanna-Kaisa Vikkula & Mozes Sze & Lisette Van Hove & Kevin Verstaen & Arne Martens & Tino , 2021. "OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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