TIFA as a crucial mediator for NLRP3 inflammasome

Ting Yang Lin, Tong You Wade Wei, Shuai Li, Shen Chih Wang, Ming He, Marcy Martin, Jiao Zhang, Tzu Pin Shentu, Han Xiao, Jian Kang, Kuei Chun Wang, Zhen Chen, Shu Chien, Ming Daw Tsai, John Y.J. Shyy

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to prooxidative and proinflammatory stimuli. We identified that TNF-α receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA) is a regulator of priming (signal 1) and activating (signal 2) signals of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of signal 1, sterol regulatory element-binding protein 2 transactivates TIFA, which in turn induces NF-κB activation and augments the transcription of NLRP3 inflammasome components. For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting signals 1 and 2.

Original languageEnglish (US)
Pages (from-to)15078-15083
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 27 2016
Externally publishedYes


  • Endothelial cells
  • Inflammasome
  • Innate immunity
  • NLRP3
  • TIFA

ASJC Scopus subject areas

  • General


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