The NEDD8 E3 ligase DCNL5 is phosphorylated by IKK alpha during Toll-like receptor activation

Yann Thomas; Daniel C Scott; Yosua Adi Kristariyanto; Jesse Rinehart; Kristopher Clark; Philip Cohen; Thimo Kurz

doi:10.1371/journal.pone.0199197

The NEDD8 E3 ligase DCNL5 is phosphorylated by IKK alpha during Toll-like receptor activation

Yann Thomas, Daniel C Scott, Yosua Adi Kristariyanto, Jesse Rinehart, Kristopher Clark, Philip Cohen, Thimo Kurz (Lead / Corresponding author)

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Abstract

The activity of Cullin-RING ubiquitin E3 ligases (CRL) is regulated by NEDD8 modification. DCN-like proteins promote Cullin neddylation as scaffold-like E3s. One DCNL, DCNL5, is highly expressed in immune tissue. Here, we provide evidence that DCNL5 may be involved in innate immunity, as it is a direct substrate of the kinase IKKα during immune signalling. We find that upon activation of Toll-like receptors, DCNL5 gets rapidly and transiently phosphorylated on a specific N-terminal serine residue (S41). This phosphorylation event is specifically mediated by IKKα and not IKKβ. Our data for the first time provides evidence that DCNL proteins are post-translationally modified in an inducible manner. Our findings also provide the first example of a DCNL member as a kinase substrate in a signalling pathway, indicating that the activity of at least some DCNLs may be regulated.

Original language	English
Article number	e0199197
Pages (from-to)	1-19
Number of pages	19
Journal	PLoS ONE
Volume	13
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0199197
Publication status	Published - 29 Jun 2018

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology
General Agricultural and Biological Sciences

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10.1371/journal.pone.0199197Licence: CC0

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This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Final published version, 6.35 MBLicence: CC0

Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases
Arthur, S. (Investigator) & Cohen, P. (Investigator)
Medical Research Council
1/04/18 → 31/03/23
Project: Research
Characterisation of Signal Transduction Pathways that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases (Programme Grant)
Cohen, P. (Investigator)
Medical Research Council
1/04/13 → 31/03/18
Project: Research

Cite this

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title = "The NEDD8 E3 ligase DCNL5 is phosphorylated by IKK alpha during Toll-like receptor activation",

abstract = "The activity of Cullin-RING ubiquitin E3 ligases (CRL) is regulated by NEDD8 modification. DCN-like proteins promote Cullin neddylation as scaffold-like E3s. One DCNL, DCNL5, is highly expressed in immune tissue. Here, we provide evidence that DCNL5 may be involved in innate immunity, as it is a direct substrate of the kinase IKKα during immune signalling. We find that upon activation of Toll-like receptors, DCNL5 gets rapidly and transiently phosphorylated on a specific N-terminal serine residue (S41). This phosphorylation event is specifically mediated by IKKα and not IKKβ. Our data for the first time provides evidence that DCNL proteins are post-translationally modified in an inducible manner. Our findings also provide the first example of a DCNL member as a kinase substrate in a signalling pathway, indicating that the activity of at least some DCNLs may be regulated.",

author = "Yann Thomas and Scott, {Daniel C} and Kristariyanto, {Yosua Adi} and Jesse Rinehart and Kristopher Clark and Philip Cohen and Thimo Kurz",

note = " This work was supported by the Medical Research Council (MC_UU_12016/7), an ERC Starting Investigator Grant (to TK), as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). We have the following interests. This study was partly supported by the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). There are no patents, products in development or marketed products to declare. ",

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AU - Thomas, Yann

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AU - Kristariyanto, Yosua Adi

AU - Rinehart, Jesse

AU - Clark, Kristopher

AU - Cohen, Philip

AU - Kurz, Thimo

N1 - This work was supported by the Medical Research Council (MC_UU_12016/7), an ERC Starting Investigator Grant (to TK), as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). We have the following interests. This study was partly supported by the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). There are no patents, products in development or marketed products to declare.

PY - 2018/6/29

Y1 - 2018/6/29

N2 - The activity of Cullin-RING ubiquitin E3 ligases (CRL) is regulated by NEDD8 modification. DCN-like proteins promote Cullin neddylation as scaffold-like E3s. One DCNL, DCNL5, is highly expressed in immune tissue. Here, we provide evidence that DCNL5 may be involved in innate immunity, as it is a direct substrate of the kinase IKKα during immune signalling. We find that upon activation of Toll-like receptors, DCNL5 gets rapidly and transiently phosphorylated on a specific N-terminal serine residue (S41). This phosphorylation event is specifically mediated by IKKα and not IKKβ. Our data for the first time provides evidence that DCNL proteins are post-translationally modified in an inducible manner. Our findings also provide the first example of a DCNL member as a kinase substrate in a signalling pathway, indicating that the activity of at least some DCNLs may be regulated.

AB - The activity of Cullin-RING ubiquitin E3 ligases (CRL) is regulated by NEDD8 modification. DCN-like proteins promote Cullin neddylation as scaffold-like E3s. One DCNL, DCNL5, is highly expressed in immune tissue. Here, we provide evidence that DCNL5 may be involved in innate immunity, as it is a direct substrate of the kinase IKKα during immune signalling. We find that upon activation of Toll-like receptors, DCNL5 gets rapidly and transiently phosphorylated on a specific N-terminal serine residue (S41). This phosphorylation event is specifically mediated by IKKα and not IKKβ. Our data for the first time provides evidence that DCNL proteins are post-translationally modified in an inducible manner. Our findings also provide the first example of a DCNL member as a kinase substrate in a signalling pathway, indicating that the activity of at least some DCNLs may be regulated.

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DO - 10.1371/journal.pone.0199197

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The NEDD8 E3 ligase DCNL5 is phosphorylated by IKK alpha during Toll-like receptor activation

Abstract

ASJC Scopus subject areas

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Projects

Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases

Characterisation of Signal Transduction Pathways that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases (Programme Grant)

Cite this