The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1

Noula Shembade, Rajeshree Pujari, Nicole S. Harhaj, Derek W. Abbott, Edward W. Harhaj

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

In response to stimulation with proinflammatory cytokines, the deubiquitinase A20 inducibly interacts with the regulatory molecules TAX1BP1, Itch and RNF11 to form the A20 ubiquitin-editing complex. However, the molecular signal that coordinates the assembly of this complex has remained elusive. Here we demonstrate that TAX1BP1 was inducibly phosphorylated on Ser593 and Ser624 in response to proinflammatory stimuli. The kinase IKKα, but not IKKβ, was required for phosphorylation of TAX1BP1 and directly phosphorylated TAX1BP1 in response to stimulation with tumor necrosis factor (TNF) or interleukin 1 (IL-1). TAX1BP1 phosphorylation was pivotal for cytokine-dependent interactions among TAX1BP1, A20, Itch and RNF11 and downregulation of signaling by the transcription factor NF-κB. IKKα therefore serves a key role in the negative feedback of NF-κB canonical signaling by orchestrating assembly of the A20 ubiquitin-editing complex to limit inflammatory gene activation.

Original languageEnglish
Pages (from-to)834-843
Number of pages10
JournalNature Immunology
Volume12
Issue number9
DOIs
StatePublished - Sep 1 2011

Fingerprint

Ubiquitin
Transcription Factors
Phosphotransferases
Phosphorylation
Cytokines
Interleukin-1
Transcriptional Activation
Down-Regulation
Tumor Necrosis Factor-alpha
Deubiquitinating Enzymes

ASJC Scopus subject areas

  • Immunology

Cite this

The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1. / Shembade, Noula; Pujari, Rajeshree; Harhaj, Nicole S.; Abbott, Derek W.; Harhaj, Edward W.

In: Nature Immunology, Vol. 12, No. 9, 01.09.2011, p. 834-843.

Research output: Contribution to journalArticle

Shembade, Noula ; Pujari, Rajeshree ; Harhaj, Nicole S. ; Abbott, Derek W. ; Harhaj, Edward W. / The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1. In: Nature Immunology. 2011 ; Vol. 12, No. 9. pp. 834-843.
@article{9aa52731f4dc4342bfb080eec5625530,
title = "The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1",
abstract = "In response to stimulation with proinflammatory cytokines, the deubiquitinase A20 inducibly interacts with the regulatory molecules TAX1BP1, Itch and RNF11 to form the A20 ubiquitin-editing complex. However, the molecular signal that coordinates the assembly of this complex has remained elusive. Here we demonstrate that TAX1BP1 was inducibly phosphorylated on Ser593 and Ser624 in response to proinflammatory stimuli. The kinase IKKα, but not IKKβ, was required for phosphorylation of TAX1BP1 and directly phosphorylated TAX1BP1 in response to stimulation with tumor necrosis factor (TNF) or interleukin 1 (IL-1). TAX1BP1 phosphorylation was pivotal for cytokine-dependent interactions among TAX1BP1, A20, Itch and RNF11 and downregulation of signaling by the transcription factor NF-κB. IKKα therefore serves a key role in the negative feedback of NF-κB canonical signaling by orchestrating assembly of the A20 ubiquitin-editing complex to limit inflammatory gene activation.",
author = "Noula Shembade and Rajeshree Pujari and Harhaj, {Nicole S.} and Abbott, {Derek W.} and Harhaj, {Edward W.}",
year = "2011",
month = "9",
day = "1",
doi = "10.1038/ni.2066",
language = "English",
volume = "12",
pages = "834--843",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1

AU - Shembade, Noula

AU - Pujari, Rajeshree

AU - Harhaj, Nicole S.

AU - Abbott, Derek W.

AU - Harhaj, Edward W.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - In response to stimulation with proinflammatory cytokines, the deubiquitinase A20 inducibly interacts with the regulatory molecules TAX1BP1, Itch and RNF11 to form the A20 ubiquitin-editing complex. However, the molecular signal that coordinates the assembly of this complex has remained elusive. Here we demonstrate that TAX1BP1 was inducibly phosphorylated on Ser593 and Ser624 in response to proinflammatory stimuli. The kinase IKKα, but not IKKβ, was required for phosphorylation of TAX1BP1 and directly phosphorylated TAX1BP1 in response to stimulation with tumor necrosis factor (TNF) or interleukin 1 (IL-1). TAX1BP1 phosphorylation was pivotal for cytokine-dependent interactions among TAX1BP1, A20, Itch and RNF11 and downregulation of signaling by the transcription factor NF-κB. IKKα therefore serves a key role in the negative feedback of NF-κB canonical signaling by orchestrating assembly of the A20 ubiquitin-editing complex to limit inflammatory gene activation.

AB - In response to stimulation with proinflammatory cytokines, the deubiquitinase A20 inducibly interacts with the regulatory molecules TAX1BP1, Itch and RNF11 to form the A20 ubiquitin-editing complex. However, the molecular signal that coordinates the assembly of this complex has remained elusive. Here we demonstrate that TAX1BP1 was inducibly phosphorylated on Ser593 and Ser624 in response to proinflammatory stimuli. The kinase IKKα, but not IKKβ, was required for phosphorylation of TAX1BP1 and directly phosphorylated TAX1BP1 in response to stimulation with tumor necrosis factor (TNF) or interleukin 1 (IL-1). TAX1BP1 phosphorylation was pivotal for cytokine-dependent interactions among TAX1BP1, A20, Itch and RNF11 and downregulation of signaling by the transcription factor NF-κB. IKKα therefore serves a key role in the negative feedback of NF-κB canonical signaling by orchestrating assembly of the A20 ubiquitin-editing complex to limit inflammatory gene activation.

UR - http://www.scopus.com/inward/record.url?scp=80051986818&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051986818&partnerID=8YFLogxK

U2 - 10.1038/ni.2066

DO - 10.1038/ni.2066

M3 - Article

C2 - 21765415

AN - SCOPUS:80051986818

VL - 12

SP - 834

EP - 843

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 9

ER -