The roles of TTP and BRF proteins in regulated mRNA decay

Sanduja, Sandhya; Blanco, Fernando F.; Dixon, Dan A.

doi:10.1002/wrna.28

Cited by 158 publications

(159 citation statements)

References 119 publications

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“…TTP regulates the expression of ARE-containing mRNAs by both promoting the degradation and repressing the translation of target mRNA (38). While the mechanisms by which TTP promotes the degradation of ARE-containing mRNAs have been extensively studied (39), the mechanism underlying TTP-mediated translational repression is not so well established. A difficulty in the studies on TTP repression of translation is that the magnitude of inhibition is relatively small.…”

Section: Discussionmentioning

confidence: 99%

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

Tao

Gao

2015

Molecular and Cellular Biology

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b Tristetraprolin (TTP) regulates the expression of AU-rich element-containing mRNAs through promoting the degradation and repressing the translation of target mRNA. While the mechanism for promoting target mRNA degradation has been extensively studied, the mechanism underlying translational repression is not well established. Here, we show that TTP recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation. TTP interacted with eIF4E2 but not with eIF4E. Overexpression of eIF4E2 enhanced TTP-mediated translational repression, and downregulation of endogenous eIF4E2 or overexpression of a truncation mutant of eIF4E2 impaired TTP-mediated translational repression. Overexpression of an eIF4E2 mutant that lost the cap-binding activity also impaired TTP's activity, suggesting that the cap-binding activity of eIF4E2 is important in TTPmediated translational repression. We further show that TTP promoted eIF4E2 binding to target mRNA. These results imply that TTP recruits eIF4E2 to compete with eIF4E to repress the translation of target mRNA. This notion is supported by the finding that downregulation of endogenous eIF4E2 increased the production of tumor necrosis factor alpha (TNF-␣) protein without affecting the mRNA levels in THP-1 cells. Collectively, these results uncover a novel mechanism by which TTP represses target mRNA translation.T ristetraprolin (TTP) plays important roles in immunity, development, and tumorigenesis by posttranscriptionally regulating the expression of a variety of genes (1). For example, TTP regulates the expression of tumor necrosis factor alpha (TNF-␣) (2). Knockout of TTP in mice results in TNF-␣ excess and causes severe immune disorders (2, 3).TTP specifically recognizes AU-rich elements (AREs), which are cis elements with tandem AUUUA-like motifs in a context rich in A and/or U, mainly located in the 3= untranslated region (3= UTR) of the mRNAs of stringently regulated genes, such as cytokine and growth factor genes and proto-oncogenes (4, 5). TTP directly binds to ARE motifs and recruits cellular mRNA decay enzymes, including the deadenylase complex CCR4-NOT, decapping complex DCP1a/DCP2, 3=-5= exoribonuclease complex exosome, and 5=-3= exoribonuclease Xrn1, to degrade target mRNAs (6)(7)(8)(9)(10)(11)(12)(13)(14). This activity of TTP is regulated by phosphorylation modification (6-14). There is increasing evidence suggesting that TTP also regulates the translation of target mRNAs. It has been reported elsewhere that TTP associates with polysomes (15, 16) and that a TTP-interacting protein, cullin 4B, promotes the loading of TTP-associated TNF-␣ mRNA complex onto polysomes (17). Recently, Qi et al. reported that TTP inhibits the translation of TNF-␣ in an ARE-dependent manner and the RNA helicase RCK is involved in this process (18). In addition, Tiedje et al. reported that TTP represses the translation of TNF-␣ through competing with HuR to bind to ARE (19). Nonetheless, detailed mechanisms underlying TTP-mediated translational repression are not well esta...

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Section: Discussionmentioning

confidence: 99%

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

Tao

Gao

2015

Molecular and Cellular Biology

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“…2A, upper left), indicating that Tob2 proteins can be phosphorylated to different extents. As a control, we showed that AP pretreatment of TTP, an ARE-binding protein known to be highly phosphorylated (Tiedje et al 2010;Sanduja et al 2011), effectively removed its phosphates. It is worth noting that the relative mobilities and intensities of the three bands for Tob2-FF differ from those for WT Tob2, suggesting a link between its phosphorylation state and its ability to interact with PABPC1.…”

Section: Phosphorylation Of Tob2 and Its Ability To Interact With Pabpc1mentioning

confidence: 98%

Phosphorylation at intrinsically disordered regions of PAM2 motif-containing proteins modulates their interactions with PABPC1 and influences mRNA fate

Huang

Chadee

Chen

et al. 2013

RNA

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Cytoplasmic poly(A)-binding protein (PABP) C1 recruits different interacting partners to regulate mRNA fate. The majority of PABP-interacting proteins contain a PAM2 motif to mediate their interactions with PABPC1. However, little is known about the regulation of these interactions or the corresponding functional consequences. Through in silico analysis, we found that PAM2 motifs are generally embedded within an extended intrinsic disorder region (IDR) and are located next to cluster(s) of potential serine (Ser) or threonine (Thr) phosphorylation sites within the IDR. We hypothesized that phosphorylation at these Ser/Thr sites regulates the interactions between PAM2-containing proteins and PABPC1. In the present study, we have tested this hypothesis using complementary approaches to increase or decrease phosphorylation. The results indicate that changing the extent of phosphorylation of three PAM2-containing proteins (Tob2, Pan3, and Tnrc6c) alters their ability to interact with PABPC1. Results from experiments using phospho-blocking or phosphomimetic mutants in PAM2-containing proteins further support our hypothesis. Moreover, the phosphomimetic mutations appreciably affected the functions of these proteins in mRNA turnover and gene silencing. Taken together, these results provide a new framework for understanding the roles of intrinsically disordered proteins in the dynamic and signal-dependent control of cytoplasmic mRNA functions.

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“…In support of this idea, one genome-wide screen found that 85% of the 380 RBPs examined were expressed in the embryonic (E13.5) and early postnatal (P0) mouse brain (McKee et al 2005). Most notable are the well-described RBPs that regulate various stages of mRNA metabolism and are important for proper neuronal differentiation and/or function, such as butyrate-response factor 1 (BRF1) (Sanduja et al 2011), neuro-oncologic ventral antigens 1/2 (NOVA 1/2) (Darnell 2006), A +U binding factor 1 (AUF1) (Gratacos and Brewer 2010), tristetraprolin (TTP) (Sanduja et al 2011), K homology splicing regulatory protein (KSRP) (Briata et al 2012), and Hu/embryonic lethal abnormal vision-like (ELAVl) ( Table 1; Pascale et al 2008). The majority of RBPs can be clustered according to their similar molecular functions, such as those belonging to the translation and turnover regulatory (TTR)-RBP group.…”

Section: Introductionmentioning

confidence: 99%

Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction

Bronicki

Jasmin

2013

RNA

111

118

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Precise control of messenger RNA (mRNA) processing and abundance are increasingly being recognized as critical for proper spatiotemporal gene expression, particularly in neurons. These regulatory events are governed by a large number of transacting factors found in neurons, most notably RNA-binding proteins (RBPs) and micro-RNAs (miRs), which bind to specific cisacting elements or structures within mRNAs. Through this binding mechanism, trans-acting factors, particularly RBPs, control all aspects of mRNA metabolism, ranging from altering the transcription rate to mediating mRNA degradation. In this context the best-characterized neuronal RBP, the Hu/ELAVl family member HuD, is emerging as a key component in multiple regulatory processes-including pre-mRNA processing, mRNA stability, and translation-governing the fate of a substantial amount of neuronal mRNAs. Through its ability to regulate mRNA metabolism of diverse groups of functionally similar genes, HuD plays important roles in neuronal development and function. Furthermore, compelling evidence indicates supplementary roles for HuD in neuronal plasticity, in particular, recovery from axonal injury, learning and memory, and multiple neurological diseases. The purpose of this review is to provide a detailed overview of the current knowledge surrounding the expression and roles of HuD in the nervous system. Additionally, we outline the present understanding of the molecular mechanisms presiding over the localization, abundance, and function of HuD in neurons.

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The roles of TTP and BRF proteins in regulated mRNA decay

Cited by 158 publications

References 119 publications

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

Phosphorylation at intrinsically disordered regions of PAM2 motif-containing proteins modulates their interactions with PABPC1 and influences mRNA fate

Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction

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