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).
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
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