Intermolecular Binding between TIFA-FHA and TIFA-pt Mediates Tumor Necrosis Factor Alpha Stimulation and NF-κB Activation

Chia Chi Flora Huang, Jui Hung Weng, Tong You Wade Wei, Pei Yu Gabriel Wu, Pang Hung Hsu, Yu Hou Chen, Shun Chang Wang, Dongyan Qin, Chin Chun Hung, Shui Tsung Chen, Andrew H.J. Wang, John Y.J. Shyy, Ming Daw Tsai

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


The forkhead-associated (FHA) domain recognizes phosphothreonine (pT) with high specificity and functional diversity. TIFA (TRAF-interacting protein with an FHA domain) is the smallest FHA-containing human protein. Its overexpression was previously suggested to provoke NF-κB activation, yet its exact roles in this signaling pathway and the underlying molecular mechanism remain unclear. Here we identify a novel threonine phosphorylation site on TIFA and show that this phosphorylated threonine (pT) binds with the FHA domain of TIFA, leading to TIFA oligomerization and TIFA-mediated NF-κB activation. Detailed analysis indicated that unphosphorylated TIFA exists as an intrinsic dimer and that the FHA-pT9 binding occurs between different dimers of TIFA. In addition, silencing of endogenous TIFA resulted in attenuation of tumor necrosis factor alpha (TNF-κ)-mediated downstream signaling. We therefore propose that the TIFA FHA-pT9 binding provides a previously unidentified link between TNF-κ stimulation and NF-κB activation. The intermolecular FHA-pT9 binding between dimers also represents a new mechanism for the FHA domain.

Original languageEnglish
Pages (from-to)2664-2673
Number of pages10
JournalMolecular and Cellular Biology
Issue number14
Publication statusPublished - Jul 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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