Intermolecular Binding between TIFA-FHA and TIFA-pT Mediates Tumor Necrosis Factor Alpha Stimulation and NF-kappa B Activation
Resource
MOLECULAR AND CELLULAR BIOLOGY, 32(14), 2664-2673
Journal
MOLECULAR AND CELLULAR BIOLOGY
Journal Volume
32
Journal Issue
14
Pages
2664-2673
Date Issued
2012
Date
2012
Author(s)
uang, Chia-Chi Flora
Weng, Jui-Hung
Wei, Tong-You Wade
Wu, Pei-Yu Gabriel
Hsu, Pang-Hung
Chen, Yu-Hou
Wang, Shun-Chang
Qin, Dongyan
Hung, Chin-Chun
Chen, Shui-Tsung
Wang, Andrew H.-J.
Shyy, John Y.-J.
Tsai, Ming-Daw
Abstract
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-α)-mediated downstream signaling. We therefore propose that the TIFA FHA-pT9 binding provides a previously unidentified link between TNF-α stimulation and NF-κB activation. The intermolecular FHA-pT9 binding between dimers also represents a new mechanism for the FHA domain.
Type
journal article
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