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J Immunol. 2017 Sep 1;199(5):1561-1566. doi: 10.4049/jimmunol.1700175. Epub 2017 Jul 24.

Cutting Edge: TRAF6 Mediates TLR/IL-1R Signaling-Induced Nontranscriptional Priming of the NLRP3 Inflammasome.

Xing Y1,2, Yao X1,2, Li H1,2,3, Xue G1,2, Guo Q1,2, Yang G3, An L3, Zhang Y1,2, Meng G4,2.

Author information

1
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
2
University of Chinese Academy of Sciences, Beijing 100039, China; and.
3
College of Life Science, Shandong Normal University, Jinan 250014, China.
4
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; gxmeng@ips.ac.cn.

Abstract

NLRP3 inflammasome activiation requires two sequential signals. The priming signal 1 from TLRs or cytokine receptors induces the transcription of NLRP3 and IL-1β, and concomitantly promotes transcription-independent activation of caspase-1. The activating signal 2 can be provided by microbial products or danger signals. In this study we found that TRAF6 is necessary for the nontranscriptional priming of NLRP3 inflammasome by TLR/IL-1R derived signals. Deficiency of TRAF6 specifically inhibited TLR/IL-1R priming-initiated caspase-1 cleavage, pyroptosis, and secretion of presynthesized IL-18. Mechanistically, TRAF6 promoted NLRP3 oligomerization as well as the interaction between NLRP3 and apoptosis-associated speck-like protein containing a CARD. Of note, the nontranscriptional priming via TRAF6 did not involve mitochondrial reactive oxygen species or the phosphorylation of Jnk, Erk, and Syk, whereas the ubiquitin E3 ligase activity of TRAF6 was required. Our findings thus extended cognition on the mechanism of NLRP3 inflammasome activation, and provided a novel target for controlling NLRP3-related diseases.

PMID:
28739881
DOI:
10.4049/jimmunol.1700175
[Indexed for MEDLINE]

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