title: TIFA as a crucial mediator for NLRP3 inflammasome.
abstract: 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.
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei 115, Taiwan.|Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Ting-Yang
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei 115, Taiwan.|Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Tong-You Wade
authors.initials: TW
authors.lastname: Wei
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin 30060, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 115, Taiwan.
authors.forename: Shen-Chih
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Ming
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Biochemistry and Molecular Biology, University of California, Riverside, CA 92521.
authors.forename: Marcy
authors.initials: M
authors.lastname: Martin
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Shentu
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Kuei-Chun
authors.initials: KC
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093 shuchien@ucsd.edu mdtsai@gate.sinica.edu.tw jshyy@ucsd.edu.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei 115, Taiwan; shuchien@ucsd.edu mdtsai@gate.sinica.edu.tw jshyy@ucsd.edu.|Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093; shuchien@ucsd.edu mdtsai@gate.sinica.edu.tw jshyy@ucsd.edu.
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D004727:Endothelium / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C446759:TIFA protein, human
keywords: NLRP3; TIFA; endothelial cells; inflammasome; innate immunity