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

David L. Boone; Emre E. Turer; Eric G. Lee; Regina Celeste Ahmad; Matthew T. Wheeler; Colleen Tsui; Paula Hurley; Marcia Chien; Sophia Chai; Osamu Hitotsumatsu; Elizabeth McNally; Cecile Pickart; Averil Ma

doi:10.1038/ni1110

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

David L. Boone, Emre E. Turer, Eric G. Lee, Regina Celeste Ahmad, Matthew T. Wheeler, Colleen Tsui, Paula Hurley, Marcia Chien, Sophia Chai, Osamu Hitotsumatsu, Elizabeth McNally, Cecile Pickart, Averil Ma

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	1052-1060
Number of pages	9
Journal	Nature immunology
Volume	5
Issue number	10
DOIs	https://doi.org/10.1038/ni1110
State	Published - Oct 2004

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/ni1110

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title = "The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses",

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.",

author = "Boone, {David L.} and Turer, {Emre E.} and Lee, {Eric G.} and Ahmad, {Regina Celeste} and Wheeler, {Matthew T.} and Colleen Tsui and Paula Hurley and Marcia Chien and Sophia Chai and Osamu Hitotsumatsu and Elizabeth McNally and Cecile Pickart and Averil Ma",

note = "Funding Information: 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{\textquoteright}s and Colitis Foundation of America (D.B.) and Medical Scientist Training Program (GM07281; E.T., R.-C.A. and M.W.).",

year = "2004",

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doi = "10.1038/ni1110",

language = "English (US)",

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AU - Boone, David L.

AU - Turer, Emre E.

AU - Lee, Eric G.

AU - Ahmad, Regina Celeste

AU - Wheeler, Matthew T.

AU - Tsui, Colleen

AU - Hurley, Paula

AU - Chien, Marcia

AU - Chai, Sophia

AU - Hitotsumatsu, Osamu

AU - McNally, Elizabeth

AU - Pickart, Cecile

AU - Ma, Averil

N1 - Funding Information: 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.).

PY - 2004/10

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N2 - 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.

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

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