ALPK1-TIFA: Sensing bacterial metabolites
Alpha protein Kinase 1 (ALPK1) and TRAF interacting forkhead-associated protein A (TIFA) form a novel and essential cytoplasmic surveillance pathway of Gram-negative bacteria.
To foster research of ALPK1 and TIFA, InvivoGen provides a collection of tools to help answer the questions that surround this novel innate immune sensing pathway:
Sensing a sugar rush - ALPK1 & TIFA
The ALPK1-TIFA signaling pathway is activated by the binding of bacterial sugars produced by both commensal and pathogenic bacteria, during the biosynthesis of lipopolysaccharide (LPS), ADP-β-d-manno-heptose (ADP-Heptose) and d-glycero-β-d-manno-heptose-1,7-bisphosphate (HBP), to ALPK1. Stimulation of ALPK1 leads to the oligomerization and activation of TIFA, which ultimately results in an NF-kB dependent pro-inflammatory response [1-3].
ADP-Heptose is delivered to the host by pathogenic bacterial injection systems such as the Type III and IV secretion systems (e.g. Yersinia pseudotuberculosis and Helicobacter pylori, respectively) [3, 4]. Importantly, ADP-Heptose can also freely penetrate the host cell membrane and access the host cytoplasm, and thus extracellular and 'non-pathogenic' bacteria can activate this pathway too [5]. Notably, HBP recognition by ALPK1 appears to be more regulated, with it requiring translocation by bacterial injection systems and needing to be enzymatically converted into ADP-Heptose-7-P to activate ALPK1[5]. Despite, recognition of HBP possibly being more selective towards pathogens, the mechanisms underlying the discrimination of commensal bacteria and pathogens remains poorly understood.
Developing our understanding of this pathway will be important in the progress of novel treatments for modulating inflammation caused by bacterial infection as well as pathologies associated with dysregulation of ALPK1-TIFA, such as vascular diseases and gastric cancer.
References:
1. Garcia-Weber, D. et al. 2018. ADP-heptose is a newly identified pathogen-associated molecular pattern of Shigella flexneri. EMBO Rep 19
2. Pfannkuch, L. et al. 2019. ADP heptose, a novel pathogen-associated molecular pattern identified in Helicobacter pylori. FASEB J, fj201802555R.
3. Zhou, P. et al. 2018. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 561, 122-126.
4. Zimmermann, S. et al. 2017. ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System. Cell Rep 20, 2384-2395.
5. Xue, Y. & Man, S.M. 2018. ALPK1: innate attraction to the sweetness of bacteria. Cell Res 28, 1125-1126.