Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action

Abstract

Changes in mRNA stability and translation are critical control points in the regulation of gene expression, particularly genes encoding growth factors, inflammatory mediators, and proto-oncogenes. Adenosine and uridine (AU)-rich elements (ARE), often located in the 3' untranslated regions (3'UTR) of mRNAs, are known to target transcripts for rapid decay. They are also involved in the regulation of mRNA stability and translation in response to extracellular cues. This review focuses on one of the best characterized ARE binding proteins, tristetraprolin (TTP), the founding member of a small family of CCCH tandem zinc finger proteins. In this survey, we have reviewed the current status of TTP interactions with mRNA and proteins, and discussed current thinking about TTP's mechanism of action to promote mRNA decay. We also review the proposed regulation of TTP's functions by phosphorylation. Finally, we have discussed emerging evidence for TTP operating as a translational regulator. This article is part of a Special Issue entitled: RNA Decay mechanisms.

Fig. 1. Papers published on TTP since 1990

The figures shows the results of the literature search described in the text; abstracts were not included. The asterisk for 2012 indicates that papers not picked up in the search on August 15, 2012, were not included.

Fig. 2. Model of the human TTP TZF domain bound to the 9-mer sequence UUAUUUAUU

The figure shows a model of the interaction between the TZF domain of human TTP and the 9-mer UUAUUUAUU, based on the original structure for human ZFP36L2 bound to the same oligonucleotide [29]. In this view, the amino-terminal zinc finger is on the right, the C-terminal zinc finger is on the left. The RNA oligonucleotide runs from left to right in the 5′ to 3′ orientation. The zinc residues are highlighted, as are certain bases in the RNA. The color is meant to demonstrate amino acid identities between this TTP sequence and the original ZFP36L2 (TIS11D) TZF domain that was used to form the original structure. As the colors become “warmer” from dark blue, they represent progressively greater chemical differences between the TTP and ZFP36L2 amino acids. Taken from [30], with permission.

Fig. 3. Model of posttranscriptional regulation by TTP

This schematic figure is intended to illustrate some of the elements of TTP function. Many protein interactions are not presented, and the specifics of the portrayed protein-protein interactions are necessarily simplistic. TTP cycles with its mRNA ligand between the translating and non-translating pool of messages [65,68,95,97]. Under conditions of low p38 activation, TTP is dephosphorylated at serines 52 and 178 (mouse) [60,66] which recruits Not1 [113]to the carboxyl end of the protein resulting in message deadenylation by the Ccr4/Caf1/Not deadenylation complex [69,70,113]. The amino terminal end of TTP recruits the decapping complex through an interaction with Dcp2 and Edc3 [120], but the specific phosphorylation status of TTP regarding this interaction has not been determined. Following p38 phosphorylation, TTP is unable to interact with Not1, and the TTP containing mRNP moves onto the polysomes. This process reportedly involves the CRL4B ubiquitin ligase component Cul4B [55]. The presence of Cul4B on the TTP containing mRNP is not dependent on p38 activity [55]. While not indicated in the figure, the translation competent TNF polysome complex may localize to the endoplasmic reticulum following signal sequence translation, and this process appears to involve HuR [127]. Through an as yet undetermined process, translation of the TTP containing mRNA ceases, and this process is reported to involve the translational repressor RCK/p54 [119]. RCK/p54 is not present on the polysomes [121] and appears to require translation initiation to operate as a translational repressor [122]. RCK/p54 interacts with a scaffolding protein, Pat1b, which also interacts with Not1 and, through Dcp1, Dcp2 [201]. Thus a deadenylation/decapping complex can form the TTP containing mRNP.