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Title: Regulation of the interaction between the RNA-binding protein, tristetraprolin, and the CCR4-CAF1 deadenylase complex for the control of inflammation
Author: Bulbrook, Daniel
ISNI:       0000 0004 6497 8585
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Tristetraprolin (TTP) is a zinc finger RNA-binding protein that binds to AU-rich elements in the 3' untranslated regions of inflammatory transcripts and targets them for rapid decay. TTP is accepted to play an important role in the resolution of the expression of inflammatory response mRNAs and the proteins they encode. TTP is induced following activation of the p38 mitogen-activated protein kinase/MK2 pathway in response to stimulation of cells with pro-inflammatory agents. The mRNA-destabilising function of TTP is transiently inactivated by the phosphorylation of TTP by MK2 allowing for a burst of inflammatory protein expression following cell stimulation followed by its resolution as MK2 activity dissipates. TTP targets mRNAs for destruction by recruiting the large CCR4-CAF1 deadenylase complex which catalyses the removal of mRNA poly-(A) tails, the first obligatory step in mRNA decay. I show that the CCR4-CAF1 subunits, CNOT2 and CNOT9, are needed for recruitment of the deadenylase complex by TTP. TTP interacts with the CNOT2 NOT box and the N-terminal domain of TTP comprises the main CNOT9-interacting region. Tryptophan residues in TTP are required for CNOT9 binding, recruitment of the CCR4-CAF1 complex and AU-rich element-mediated mRNA decay. I provide direct biochemical evidence that phosphorylation of Ser-52 and Ser-178 of TTP by MK2 promotes the binding of 14-3-3 and that this prevents TTP: CNOT2/CNOT9 interactions. Thus I define a new mechanism whereby TTP targets inflammatory mRNAs for decay and provide the first formal demonstration that 14-3-3 is responsible for inactivation of TTP-directed mRNA decay upon activation of the p38 MAPK/MK2 pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available