Reactome | ALPK1 phosphorylates TIFA

ALPK1 phosphorylates TIFA

Stable Identifier

R-HSA-9645535

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA) was reported to trigger NF-kappa B mediated inflammatory responses to Helicobacter pylori, Shigella flexneri, Yersinia pseudotuberculosis infections (Gall A et al. 2017; Milivojevic M et al. 2017; Gaudet RG et al. 2017; García‐Weber D et al. 2018; Zhou P et al. 2018). During infection, ADP-heptose-activated alpha protein kinase 1 (ALPK1) binds and phosphorylates TIFA at threonine 9 (T9) (Zhou P et al. 2018). Defective NF-κB activation in TIFA -/- human embryonic kidney 293T (HEK293T) cells was restored by wild-type TIFA but not by the non-phosphorylatable T9A TIFA variant upon H. pylori, S. flexneri, Y. pseudotuberculosis infections (Zimmermann S et al. 2017; Gaudet RG et al. 2017; Zhou P et al. 2018). Moreover, T9A TIFA variant was unable to oligomerize preventing the S. flexneri- induced formation of the TIFA:TRAF6:TAK1-Ub complex in TIFA -/- HEK293T cells (Gaudet RG et al. 2015, 2017). Unphosphorylated TIFA is thought to exist as an intrinsic dimer in solution (Huang CC et al. 2012). When T9 is phosphorylated, this is recognized by the FHA domain of other TIFA dimers leading to its oligomerization (Huang CC et al. 2012). Oligomerized TIFA promotes activation of an innate immune response by inducing the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 (MAP3K7) and IKK (Ea CK et al. 2004).

Literature References

PubMed ID	Title	Journal	Year
30111836	Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose Zhou, P, She, Y, Dong, N, Li, P, He, H, Borio, A, Wu, Q, Lu, S, Ding, X, Cao, Y, Xu, Y, Gao, W, Dong, M, Ding, J, Wang, DC, Zamyatina, A, Shao, F	Nature	2018