Intermolecular binding between TIFA-FHA & TIFA-pT9 mediates TNF-alpha stimulation & NF-kappaB activation
Date Issued
2012
Date
2012
Author(s)
Huang, Chia-Chi
Abstract
The forkhead-associated (FHA) domain recognizes phosphothreonine (pT) with high specificity and functional diversity. TIFA (TRAF-interacting protein with a FHA domain) is the smallest FHA-containing human protein. Its over-expression was previously suggested to provoke NF-kappaB activation, yet its exact roles in this signaling pathway and the underlying molecular mechanism remain unclear. Here we identify a novel phosphorylated threonine site, threonine 9 (pT9), on TIFA and show that this phosphorylation site binds with the FHA domain of TIFA, leading to TIFA oligomerization and TIFA-mediated NF-kappaB 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 TNF-alpha-mediated downstream signaling. We therefore propose that the TIFA FHA-pT9 binding provides a previously unidentified link between TNF-alpha stimulation and NF-kappaB activation. The intermolecular FHA-pT9 binding between dimers also represents a new mechanism for the FHA domain.
Subjects
FHA domain
NF-kappaB
phosphothreonine
TNF-alpha-mediated signaling
Type
thesis
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