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Hrdinka, M; Fiil, BK; Zucca, M; Leske, D; Bagola, K; Yabal, M; Elliott, PR; Damgaard, RB; Komander, D; Jost, PJ; Gyrd-Hansen, M.
CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling.
Cell Rep. 2016; 14(12):2846-2858 Doi: 10.1016/j.celrep.2016.02.062 [OPEN ACCESS]
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Jost Philipp

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Innate immune signaling relies on the deposition of non-degradative polyubiquitin at receptor-signaling complexes, but how these ubiquitin modifications are regulated by deubiquitinases remains incompletely understood. Met1-linked ubiquitin (Met1-Ub) is assembled by the linear ubiquitin assembly complex (LUBAC), and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP. In this study, we report that HOIP also interacts with the deubiquitinase CYLD but that CYLD does not regulate ubiquitination of LUBAC components. Instead, CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 to restrict signaling and cytokine production. Accordingly, Met1-Ub and Lys63-Ub were individually required for productive NOD2 signaling. Our study thus suggests that LUBAC, through its associated deubiquitinases, coordinates the deposition of not only Met1-Ub but also Lys63-Ub to ensure an appropriate response to innate immune receptor activation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Catalytic Domain -
Cell Line, Tumor -
Cytokines - metabolism
Deubiquitinating Enzymes - antagonists & inhibitors
Deubiquitinating Enzymes - genetics
Deubiquitinating Enzymes - metabolism
Endopeptidases - chemistry
Endopeptidases - genetics
Endopeptidases - metabolism
HEK293 Cells -
Humans -
Immunity, Innate -
Lysine - chemistry
Lysine - metabolism
Methionine - chemistry
Methionine - metabolism
Mutagenesis, Site-Directed -
NF-kappa B - metabolism
RNA Interference -
RNA, Small Interfering - metabolism
Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism
Signal Transduction -
Ubiquitin - chemistry
Ubiquitin - genetics
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - antagonists & inhibitors
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
Ubiquitination -

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