The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20

Noula Shembade, Nicole S. Harhaj, Kislay Parvatiyar, Neal G. Copeland, Nancy A. Jenkins, Lydia E. Matesic, Edward W. Harhaj

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-κB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1. Furthermore, the Tax oncoprotein of human T cell leukemia virus type I targeted this complex for inactivation by disrupting the interaction among TAX1BP1, A20 and Itch. Thus, our studies show a previously unappreciated complexity of A20 substrate recognition and inactivation whereby TAX1BP1 and Itch function as essential subunits of an A20 ubiquitin-editing complex.

Original languageEnglish
Pages (from-to)254-262
Number of pages9
JournalNature Immunology
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2008

Fingerprint

Ubiquitin-Protein Ligases
Ubiquitin
Human T-lymphotropic virus 1
Tumor Necrosis Factor Receptors
Oncogene Proteins
Enzymes
Transcription Factors
Cytokines
Inflammation

ASJC Scopus subject areas

  • Immunology

Cite this

The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. / Shembade, Noula; Harhaj, Nicole S.; Parvatiyar, Kislay; Copeland, Neal G.; Jenkins, Nancy A.; Matesic, Lydia E.; Harhaj, Edward W.

In: Nature Immunology, Vol. 9, No. 3, 01.03.2008, p. 254-262.

Research output: Contribution to journalArticle

Shembade, Noula ; Harhaj, Nicole S. ; Parvatiyar, Kislay ; Copeland, Neal G. ; Jenkins, Nancy A. ; Matesic, Lydia E. ; Harhaj, Edward W. / The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. In: Nature Immunology. 2008 ; Vol. 9, No. 3. pp. 254-262.
@article{dc382beab7274365ba7bfdcc6a83caa6,
title = "The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20",
abstract = "The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-κB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1. Furthermore, the Tax oncoprotein of human T cell leukemia virus type I targeted this complex for inactivation by disrupting the interaction among TAX1BP1, A20 and Itch. Thus, our studies show a previously unappreciated complexity of A20 substrate recognition and inactivation whereby TAX1BP1 and Itch function as essential subunits of an A20 ubiquitin-editing complex.",
author = "Noula Shembade and Harhaj, {Nicole S.} and Kislay Parvatiyar and Copeland, {Neal G.} and Jenkins, {Nancy A.} and Matesic, {Lydia E.} and Harhaj, {Edward W.}",
year = "2008",
month = "3",
day = "1",
doi = "10.1038/ni1563",
language = "English",
volume = "9",
pages = "254--262",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20

AU - Shembade, Noula

AU - Harhaj, Nicole S.

AU - Parvatiyar, Kislay

AU - Copeland, Neal G.

AU - Jenkins, Nancy A.

AU - Matesic, Lydia E.

AU - Harhaj, Edward W.

PY - 2008/3/1

Y1 - 2008/3/1

N2 - The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-κB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1. Furthermore, the Tax oncoprotein of human T cell leukemia virus type I targeted this complex for inactivation by disrupting the interaction among TAX1BP1, A20 and Itch. Thus, our studies show a previously unappreciated complexity of A20 substrate recognition and inactivation whereby TAX1BP1 and Itch function as essential subunits of an A20 ubiquitin-editing complex.

AB - The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-κB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1. Furthermore, the Tax oncoprotein of human T cell leukemia virus type I targeted this complex for inactivation by disrupting the interaction among TAX1BP1, A20 and Itch. Thus, our studies show a previously unappreciated complexity of A20 substrate recognition and inactivation whereby TAX1BP1 and Itch function as essential subunits of an A20 ubiquitin-editing complex.

UR - http://www.scopus.com/inward/record.url?scp=39449083378&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39449083378&partnerID=8YFLogxK

U2 - 10.1038/ni1563

DO - 10.1038/ni1563

M3 - Article

VL - 9

SP - 254

EP - 262

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 3

ER -