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pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase

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  • Jian An

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Charles M. Ponthier

    (Dana-Farber Cancer Institute)

  • Ragna Sack

    (Friedrich Miescher Institute for Biomedical Research)

  • Jan Seebacher

    (Friedrich Miescher Institute for Biomedical Research)

  • Michael B. Stadler

    (Friedrich Miescher Institute for Biomedical Research
    Swiss Institute of Bioinformatics)

  • Katherine A. Donovan

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Eric S. Fischer

    (Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignancies. It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKZF1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist. Using a pulse-chase SILAC mass spectrometry-based proteomics approach, we demonstrate that lenalidomide induces the ubiquitination and degradation of ZFP91. We establish ZFP91 as a bona fide IMiD-dependent CRL4CRBN substrate and further show that ZFP91 harbours a zinc finger (ZnF) motif, related to the IKZF1/3 ZnF, critical for IMiD-dependent CRBN binding. These findings demonstrate that single time point pulse-chase SILAC mass spectrometry-based proteomics (pSILAC MS) is a sensitive approach for target identification of small molecules inducing selective protein degradation.

Suggested Citation

  • Jian An & Charles M. Ponthier & Ragna Sack & Jan Seebacher & Michael B. Stadler & Katherine A. Donovan & Eric S. Fischer, 2017. "pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15398
    DOI: 10.1038/ncomms15398
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    Cited by:

    1. Gisele Nishiguchi & Lauren G. Mascibroda & Sarah M. Young & Elizabeth A. Caine & Sherif Abdelhamed & Jeffrey J. Kooijman & Darcie J. Miller & Sourav Das & Kevin McGowan & Anand Mayasundari & Zhe Shi &, 2024. "Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Satoshi Yamanaka & Hirotake Furihata & Yuta Yanagihara & Akihito Taya & Takato Nagasaka & Mai Usui & Koya Nagaoka & Yuki Shoya & Kohei Nishino & Shuhei Yoshida & Hidetaka Kosako & Masaru Tanokura & Ta, 2023. "Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Zefeng Wang & Shabnam Shaabani & Xiang Gao & Yuen Lam Dora Ng & Valeriia Sapozhnikova & Philipp Mertins & Jan Krönke & Alexander Dömling, 2023. "Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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