The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses

  • A Corrigendum to this article was published on 01 January 2005

Abstract

A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)–induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor–induced activity of the transcription factor NF-κB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.

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Figure 1: A20 is essential for the prevention of TNFR1-independent proinflammatory signals.
Figure 2: A20 is essential for the prevention of TNF-independent proinflammatory signals.
Figure 3: A20 is critical for the regulation of macrophage responses in vivo and protecting against septic shock.
Figure 4: A20 regulates macrophage responses to TLR ligands.
Figure 5: A20 is essential for the termination of TLR-induced IKK activity.
Figure 6: A20 is not required for endotoxin tolerance.
Figure 7: A20 is a deubiquitinating enzyme that modifies TRAF6 ubiquitination.

Change history

  • 12 September 2004

    added footnote to XML; appended incorrect AOP PDF with note; added notes in xml for all Fig 7 instances; corrected online date will be added to issue version

Notes

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    *Note: In the version of this article originally published online, the last sentence of the legend to Figure 7 was incorrect and should be deleted. This error has been corrected for the HTML and print versions of this article.

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Acknowledgements

We thank I. Wertz, V. Dixit, and B. Malynn for reagents, discussions and critical reading of the manuscript. Supported by the National Institutes of Health (RO1AI53224 and R01DK52751 to A.M.), Digestive Disease Research Center (DK42086), Burroughs Welcome (E.M.), Crohn's and Colitis Foundation of America (D.B.) and Medical Scientist Training Program (GM07281; E.T., R.-C.A. and M.W.).

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Correspondence to Averil Ma.

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