TIFA oligomerization

Stable Identifier
Homo sapiens
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TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA) was reported to induce NF-kappa B mediated inflammatory responses to Helicobacter pylori, Shigella flexneri, Yersinia pseudotuberculosis and other infections in various human cells (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, alpha protein kinase 1 (ALPK1) phosphorylates TIFA at threonine 9 (T9) (Zimmerman S et al. 2017; Milivojevic M et al. 2017; Zhou P et al. 2018). 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 TIFA self-oligomerization (Huang CC et al. 2012). FHA domain is the only signaling domain that recognizes phosphothreonine (pT) specifically (Hammet A et al. 2003). 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). Structural studies of the truncated TIFA in complex with its T9 phosphorylated N-terminal peptide (1-15) confirmed that the pT9–FHA domain interaction can occur only between different sets of dimers rather than between the two protomers within a dimer (Weng JH et al. 2015). Glycerol-gradient ultracentrifugation analysis revealed that a very small amount of TIFA formed oligomers and only these oligomeric forms of TIFA were able to activate IKK in vitro (Ea CK et al. 2004). Mutations in the FHA domain caused a shift in the distribution of the molecular sizes of TIFA toward the middle of the gradient, but none of the fractions containing TIFA-FHA mutant was able to activate IKK (Ea CK et al. 2004). Homo-oligomerization of TIFA was also observed when glutathione S-transferase (GST)- tagged TIFA or its mutants were co-expressed with FLAG-TIFA in human embryonic kidney 293T (HEK293T) cells followed by GST-pull down assay (Takatsuna H et al. 2003). TIFA aggregation was measured by clear-native PAGE (CN-PAGE) in 1XFLAG-TIFA expressing HEK293T cells infected with Salmonella for 6 hr (Gaudet RG et al. 2017). ALPK1 depletion completely prevented the formation of TIFA oligomers after Shigella flexneri infection in HeLa cells (Milivojevic M et al. 2017). TIFA oligomerization was restored by overexpressing a siRNA-resistant full length ALPK1 construct. In contrast, overexpressing a construct deleted of the kinase domain of ALPK1 failed to do so, showing that the kinase domain of ALPK1 is essential for the regulation of TIFA oligomerization (Milivojevic M et al. 2017).

Literature References
PubMed ID Title Journal Year
26389808 Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses

Huang, CC, Wang, I, Ho, MR, Lim, LH, Hsieh, YC, Tsai, MD, Chen, CJ, Chen, YH, Weng, JH, Wei, TY, Huang, KF

Biochemistry 2015
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