The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals

被引:292
作者
Hitotsumatsu, Osamu [1 ]
Ahmad, Regina-Celeste [1 ]
Tavares, Rita [1 ]
Wang, Min [1 ]
Philpott, Dana [2 ]
Turer, Emre E. [1 ]
Lee, Bettina L. [1 ]
Shiffin, Nataliya [1 ]
Advincula, Rommel [1 ]
Malynn, Barbara A. [1 ]
Werts, Catherine [2 ]
Ma, Averil [1 ]
机构
[1] Univ Calif San Francisco, Dept Med, Div Gastroenterol, Program Biomed Sci,UCSF Colitis Ctr, San Francisco, CA 94143 USA
[2] Inst Pasteur, Grp Immunite Innee Signalisat, Paris, France
关键词
D O I
10.1016/j.immuni.2008.02.002
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 NF kappa B 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 NF kappa B 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.
引用
收藏
页码:381 / 390
页数:10
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