通过模式识别受体(PRR)对病原体相关分子模式(PAMPs)的免疫识别通常激活促炎核因子κB (NF-κB)信号通路。脂多糖(LPS)是一种众所周知的由革兰氏阴性菌产生的PAMP。LPS可被toll样受体4 (TLR4)识别，是NF-κB炎症反应的强激活因子(Akashi S et al. 2003)。小鼠caspase-11和相关的人caspase-4和caspase-5也能在胞质中识别LPS，它能刺激细胞的焦亡，这是一种促炎的细胞死亡形式(Kayagaki N et al. 2011;Shi J et al. 2015)。据报道，LPS生物合成的关键代谢中间体，d-甘油-β-d-甘露-庚糖1,7-二磷酸(HBP)和ADP-甘油-β-d-甘露-庚糖(ADP-heptose)可激活NF-κB通路并触发先天性免疫应答(Milivojevic M et al. 2017;Zimmermann S等人2017;周鹏等。2018;Garcia-Weber D;2018）. ADP-heptose but not HBP can enter host cells autonomously (Zhou P et al. 2018). During infection, ADP-heptose or HBP translocate into the host cytosol where their presence is sensed by alpha-protein kinase 1 (ALPK1) (Zimmermann S et al. 2017; Zhou P et al. 2018). ADP-heptose directly binds and activates ALPK1 (Garcia-Weber D et al. 2018; Zhou P et al. 2018); instead, HBP is converted by host-derived adenylyltransferases, such as nicotinamide nucleotide adenylyltransferases, to ADP-heptose 7-P, a substrate which can then activate ALPK1 (Zhou P et al. 2018). The ADP-heptose binding to ALPK1 is thought to trigger conformational changes and stimulate the kinase domain of ALPK1 (Zhou P et al. 2018). ALPK1 kinase activity in turn leads to the phosphorylation-dependent oligomerization of the tumor necrosis factor (TNF-α) receptor–associated factor (TRAF)–interacting protein with the forkhead-associated domain (TIFA) (Zimmermann S et al. 2017; Zhou P et al. 2018). This process activates TRAF6 oligomerization and ubiquitination, and the recruitment of transforming growth factor β-activated kinase 1 (TAK1)-binding protein 2 (TAB2), a component of the TAK1 (MAP3K7) complex (Ea CK et al. 2004; Gaudet RG et al. 2017). This TIFA oligomer signaling platform was given the term: TIFAsome. TIFAsome-activated TAK1 induces NF-κB nuclear translocation and proinflammatory gene expression. The ALPK1-TIFA signaling pathway has been identified in human embryonic kidney cells, intestinal epithelial cells, gastric cells and cervical cancer cells (Gaudet RG et al. 2015, 2017; Stein SC et al. 2017; Gall A et al. 2017; Zimmermann S et al. 2017; Milivojevic M et al. 2017; Zhou P et al. 2018). In vivo studies demonstrate that ADP-heptose and Burkholderia cenocepacia trigger massive inflammatory responses with increased production of several NF-κB-dependent cytokines and chemokines in wild type (WT), but not in Alpk1-/- mice (Zhou P et al. 2018).

这个Reactome模块描述了ALPK1作为细菌adp -七糖的胞质固有免疫受体。