OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin

Kirstin Keusekotten, Paul Ronald Elliott, Laura Glockner, Berthe Katrine Fiil, Rune Busk Damgaard, Yogesh Kulathu, Tobias Wauer, Manuela Kathrin Hospenthal, Mads Gyrd-Hansen, Daniel Krappmann, Kay Hofmann, David Komander

    Research output: Contribution to journalArticle

    211 Citations (Scopus)

    Abstract

    The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor ?B (NF-?B) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-?B responses to LUBAC, TNFa, and poly(I:C) and sensitizes cells to TNFa-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFa-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.
    Original languageEnglish
    Pages (from-to)1312-1326
    Number of pages15
    JournalCell
    Volume153
    Issue number6
    DOIs
    Publication statusPublished - 6 Jun 2013

    Keywords

    • Animals
    • Models, Molecular
    • Humans
    • Polyubiquitin
    • Amino Acid Sequence
    • Endopeptidases
    • Sequence Alignment
    • Molecular Sequence Data
    • Cytokines
    • Crystallography, X-Ray
    • Protein Structure, Tertiary
    • Signal Transduction
    • Catalysis

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  • Cite this

    Keusekotten, K., Elliott, P. R., Glockner, L., Fiil, B. K., Damgaard, R. B., Kulathu, Y., Wauer, T., Hospenthal, M. K., Gyrd-Hansen, M., Krappmann, D., Hofmann, K., & Komander, D. (2013). OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell, 153(6), 1312-1326. https://doi.org/10.1016/j.cell.2013.05.014