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.endothelial cells | inflammasome | innate immunity | NLRP3 | TIFA

TRAF-interacting protein with forkhead-associated domain (TIFA) transduces DNA damage–induced activation of NF-κB

“…This observation was consistent with the binding preference of the FHA domain for phosphorylated threonine over phosphorylated serine (11,12,28). Indeed, we found threonine 9 of TIFA was phosphorylated in response to DNA insults, and the FHA-pThr interaction was crucial for TIFA-mediated NF-B activation in genotoxic conditions as its roles in other inflammatory pathways (14,23,29). Benefits of chromatin enrichment of TIFA for NF-B activation could be easily grasped with the fact that oligomerization is a prevailing mechanism for ubiquitination-based efficient assembly of IKK complex (4,5).…”

“…Another interesting finding from this study was the common Thr-9 phosphorylation events for both canonical inflammation and DNA damage-signaling pathways, despite that different kinases might be involved (29,33). Although the whole picture for the differences of these cascades was currently unknown, nucleus translocation and chromatin enrichment of TIFA could only be observed in DNA-damaged conditions, but not in inflammatory cascades, suggested that additional regulations exist to account for DNA damageinduced subcellular translocation.…”

ADP heptose, a novel pathogen‐associated molecular pattern identified in Helicobacter pylori

“…Stimulation of NF-κB activation by common inducers, such as IL-1β or TNF-α, involves canonical pathways, whereas stimulation by ADP heptose and HBP leads to the formation of the large TIFAsome complex, which, as we revealed previously (9), associates multiple signaling molecules that may have a capacity to stimulate additional routes, such as MAPK pathways. Likewise, a recent report showed that signaling via TIFA can lead to activation of the inflammasome (28). It will certainly be interesting to explore the spectrum of ALPK1-TIFA–dependent pathways in greater depth.…”

Heptose 1,7-Bisphosphate Directed TIFA Oligomerization: A Novel PAMP-Recognizing Signaling Platform in the Control of Bacterial Infections

“…24 It was first described that TIFA plays a crucial role in NLRP3 inflammasome priming and activation. 25 In this study, arteries and cultured endothelial cells exposed to mechanical stress and oxidized low-density lipoprotein have increased the activation of sterol regulatory elementbinding protein 2 (SREBP2) to enhance the transcription of TIFA and NLRP3. In addition, SREBP2-mediated overexpression of TIFA caused NF-kB activation, which was also contributing to the overexpression of NLRP3 and inflammasome components, such as the inactive proforms of caspase-1 and IL-1b, respectively.…”