Inhibition of nf-kb signaling by a20 through disruption of ubiquitin enzyme complexes

Noula Shembade, Averil Ma, Edward Harhaj

Research output: Contribution to journalArticle

359 Citations (Scopus)

Abstract

A20 negatively regulates inflammation by inhibiting the nuclear factor kB (NF-kB) transcription factor in the tumor necrosis factor receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFRl by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-kB signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and clAPl by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubd3 and UbcH5c. A20, together with the regulatory molecule TAXlBPl, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest a mechanism of A20 action in the inhibition of inflammatory signaling pathways.

Original languageEnglish (US)
Pages (from-to)1135-1139
Number of pages5
JournalScience
Volume327
Issue number5969
DOIs
StatePublished - Feb 26 2010

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Ubiquitin-Protein Ligases
Ubiquitin
TNF Receptor-Associated Factor 2
TNF Receptor-Associated Factor 6
Ubiquitin-Conjugating Enzymes
Tumor Necrosis Factor Receptors
Toll-Like Receptors
Ubiquitination
Proteasome Endopeptidase Complex
Enzymes
Transcription Factors
Inflammation
Deubiquitinating Enzymes

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • General

Cite this

Shembade, Noula ; Ma, Averil ; Harhaj, Edward. / Inhibition of nf-kb signaling by a20 through disruption of ubiquitin enzyme complexes. In: Science. 2010 ; Vol. 327, No. 5969. pp. 1135-1139.
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Inhibition of nf-kb signaling by a20 through disruption of ubiquitin enzyme complexes. / Shembade, Noula; Ma, Averil; Harhaj, Edward.

In: Science, Vol. 327, No. 5969, 26.02.2010, p. 1135-1139.

Research output: Contribution to journalArticle

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