ALPK1:ADP-heptose binds TIFA

Stable Identifier
Reaction [binding]
Homo sapiens
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A fluorescence-activated cell sorting (FACS)-based, genome-wide CRISPR-Cas9 screen on a HEK293T NF-κB reporter cell line identified alpha protein kinase 1 (ALPK1), tumor necrosis factor (TNF-α) receptor–associated factor (TRAF)–interacting protein with the forkhead-associated domain (TIFA) and TRAF6 as mediators of NF-kB activation induced by bacterial ADP L-glycero-β-d-manno-heptose (ADP-heptose) or by Yersinia pseudotuberculosis (Zhou P et al. 2018). ADP-heptose is metabolic intermediate in the lipopolysaccharide (LPS) biosynthesis, which is present in all Gram-negative and some Gram-positive bacteria (Tang W et al. 2018). ADP-heptose stimulated coimmunoprecipitation of TIFA with ALPK1 and TRAF6 (Zhou P et al. 2018). Deletion of ALPK1 or TIFA abolished ADP-heptose-induced NF-κB activation and cytokine expression in HEK293T cells. Defective NF-κB activation in ADP-heptose-treated TIFA-/- HEK293T cells was restored by wild-type TIFA but not by a T9A mutant (Zhou P et al. 2018). Further, ALPK1 kinase activity was required for ADP-heptose-induced phosphorylation of TIFA in HEK293T cells, thus indicating that ALPK1 acts upstream of TIFA (Zhou P et al. 2018). Similarly, ADP‐heptose sensing and TIFA oligomerization was ALPK1‐dependent during Shigella flexneri infection (Garcia-Weber D et al. 2018). These findings are supported by studies showing that d-glycero-β-d-manno-heptose 1,7-bisphosphate (HBP), another intermediate of the LPS biosynthesis pathway, induced activation of ALPK1-TIFA-dependent NF-κB signaling in host cells upon Neisseria meningitidis, Shigella flexneri, Salmonella enterica serovar Typhimurium or Helicobacter pylori (H. pylori) infections (Zimmermann S et al. 2017; Milivojevic M et al. 2017; Gaudet RG et al. 2017). It is important to note that HBP is converted by host-derived adenylyltransferases, such as nicotinamide nucleotide adenylyltransferase, to ADP-heptose 7-P, a substrate which can then activate ALPK1 and the downstream NF-κB response (Zhou P et al. 2018).
Literature References
PubMed ID Title Journal Year
30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose

Wang, DC, Lu, S, Li, P, Dong, N, Zamyatina, A, Borio, A, She, Y, Wu, Q, He, H, Zhou, P, Ding, J, Ding, X, Shao, F, Cao, Y, Dong, M, Gao, W, Xu, Y

Nature 2018
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