The Ubiquitin-Editing Enzyme A20 Restricts Nucleotide-Binding Oligomerization Domain Containing 2-Triggered Signals

Osamu Hitotsumatsu, Regina Celeste Ahmad, Rita Tavares, Min Wang, Dana Philpott, Emre E. Turer, Bettina L. Lee, Nataliya Shiffin, Rommel Advincula, Barbara A. Malynn, Catherine Werts, Averil Ma

Research output: Contribution to journalArticle

231 Scopus citations

Abstract

Muramyl dipeptide (MDP), a product of bacterial cell-wall peptidoglycan, activates innate immune cells by stimulating nucleotide-binding oligomerization domain containing 2 (NOD2) -dependent activation of the transcription factor NFκB and transcription of proinflammatory genes. A20 is a ubiquitin-modifying enzyme that restricts tumor necrosis factor (TNF) receptor and Toll-like receptor (TLR) -induced signals. We now show that MDP induces ubiquitylation of receptor- interacting protein 2 (RIP2) in primary macrophages. A20-deficient cells exhibit dramatically amplified responses to MDP, including increased RIP2 ubiquitylation, prolonged NFκB signaling, and increased production of proinflammatory cytokines. In addition, in vivo responses to MDP are exaggerated in A20-deficient mice and in chimeric mice bearing A20-deficient hematopoietic cells. These exaggerated responses occur independently of the TLR adaptors MyD88 and TRIF as well as TNF signals. These findings indicate that A20 directly restricts NOD2 induced signals in vitro and in vivo, and provide new insights into how these signals are physiologically restricted.

Original languageEnglish (US)
Pages (from-to)381-390
Number of pages10
JournalImmunity
Volume28
Issue number3
DOIs
StatePublished - Mar 14 2008

Keywords

  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Hitotsumatsu, O., Ahmad, R. C., Tavares, R., Wang, M., Philpott, D., Turer, E. E., Lee, B. L., Shiffin, N., Advincula, R., Malynn, B. A., Werts, C., & Ma, A. (2008). The Ubiquitin-Editing Enzyme A20 Restricts Nucleotide-Binding Oligomerization Domain Containing 2-Triggered Signals. Immunity, 28(3), 381-390. https://doi.org/10.1016/j.immuni.2008.02.002