CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling. / Hrdinka, Matous; Fiil, Berthe Katrine; Zucca, Mattia; Leske, Derek; Bagola, Katrin; Yabal, Monica; Elliott, Paul R; Damgaard, Rune Busk; Komander, David; Jost, Philipp J; Gyrd-Hansen, Mads.

In: Cell Reports, Vol. 14, No. 12, 29.03.2016, p. 2846-58.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hrdinka, M, Fiil, BK, Zucca, M, Leske, D, Bagola, K, Yabal, M, Elliott, PR, Damgaard, RB, Komander, D, Jost, PJ & Gyrd-Hansen, M 2016, 'CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling', Cell Reports, vol. 14, no. 12, pp. 2846-58. https://doi.org/10.1016/j.celrep.2016.02.062

APA

Hrdinka, M., Fiil, B. K., Zucca, M., Leske, D., Bagola, K., Yabal, M., Elliott, P. R., Damgaard, R. B., Komander, D., Jost, P. J., & Gyrd-Hansen, M. (2016). CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling. Cell Reports, 14(12), 2846-58. https://doi.org/10.1016/j.celrep.2016.02.062

Vancouver

Hrdinka M, Fiil BK, Zucca M, Leske D, Bagola K, Yabal M et al. CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling. Cell Reports. 2016 Mar 29;14(12):2846-58. https://doi.org/10.1016/j.celrep.2016.02.062

Author

Hrdinka, Matous ; Fiil, Berthe Katrine ; Zucca, Mattia ; Leske, Derek ; Bagola, Katrin ; Yabal, Monica ; Elliott, Paul R ; Damgaard, Rune Busk ; Komander, David ; Jost, Philipp J ; Gyrd-Hansen, Mads. / CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling. In: Cell Reports. 2016 ; Vol. 14, No. 12. pp. 2846-58.

Bibtex

@article{46dd7a0cd2ad46a2acd9b9936caf4ee0,
title = "CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling",
abstract = "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. ",
keywords = "Catalytic Domain, Cell Line, Tumor, Cytokines/metabolism, Deubiquitinating Enzymes/antagonists & inhibitors, Endopeptidases/chemistry, HEK293 Cells, Humans, Immunity, Innate, Lysine/chemistry, Methionine/chemistry, 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-Protein Ligases/antagonists & inhibitors, Ubiquitination",
author = "Matous Hrdinka and Fiil, {Berthe Katrine} and Mattia Zucca and Derek Leske and Katrin Bagola and Monica Yabal and Elliott, {Paul R} and Damgaard, {Rune Busk} and David Komander and Jost, {Philipp J} and Mads Gyrd-Hansen",
note = "Copyright {\textcopyright} 2016 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2016",
month = mar,
day = "29",
doi = "10.1016/j.celrep.2016.02.062",
language = "English",
volume = "14",
pages = "2846--58",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",

}

RIS

TY - JOUR

T1 - CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

AU - Hrdinka, Matous

AU - Fiil, Berthe Katrine

AU - Zucca, Mattia

AU - Leske, Derek

AU - Bagola, Katrin

AU - Yabal, Monica

AU - Elliott, Paul R

AU - Damgaard, Rune Busk

AU - Komander, David

AU - Jost, Philipp J

AU - Gyrd-Hansen, Mads

N1 - Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2016/3/29

Y1 - 2016/3/29

N2 - 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.

AB - 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.

KW - Catalytic Domain

KW - Cell Line, Tumor

KW - Cytokines/metabolism

KW - Deubiquitinating Enzymes/antagonists & inhibitors

KW - Endopeptidases/chemistry

KW - HEK293 Cells

KW - Humans

KW - Immunity, Innate

KW - Lysine/chemistry

KW - Methionine/chemistry

KW - Mutagenesis, Site-Directed

KW - NF-kappa B/metabolism

KW - RNA Interference

KW - RNA, Small Interfering/metabolism

KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism

KW - Signal Transduction

KW - Ubiquitin/chemistry

KW - Ubiquitin-Protein Ligases/antagonists & inhibitors

KW - Ubiquitination

U2 - 10.1016/j.celrep.2016.02.062

DO - 10.1016/j.celrep.2016.02.062

M3 - Journal article

C2 - 26997266

VL - 14

SP - 2846

EP - 2858

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 12

ER -

ID: 280718115