An Ancient Family of RNA-Binding Proteins: Still Important!

Wells, Melissa L.; Perera, Lalith; Blackshear, Perry J.

doi:10.1016/j.tibs.2016.12.003

Cited by 57 publications

(62 citation statements)

References 70 publications

(89 reference statements)

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“…For instance, the CPEB complex, best described in Xenopus oocytes [18], binds the CPE motif in the 3' untranslated region (UTR) of maternal transcripts through CPEB1, thus controlling their storage and their translational activation upon hormone stimulation [19]. Additional examples include the proteins which bind 3'UTR AU-rich elements (ARE), such as HuR and TTP, to control translation and decay, and play key roles in inflammation, apoptosis and cancer [20]. Protein-binding motifs are generally not unique but are rather defined as consensus sequence elements.…”

Section: Introductionmentioning

confidence: 99%

GC content shapes mRNA decay and storage in human cells

Courel

Clément

Foretek

et al. 2018

Preprint

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Control of protein expression results from the fine tuning of mRNA synthesis, decay and translation. These processes, which are controlled by a large number of RNA-binding proteins and by localization in RNP granules such as P-bodies, appear often intimately linked although the rules of this interplay are not well understood. In this study, we combined our recent P-body transcriptome with various transcriptomes obtained following silencing of broadly acting mRNA decay and repression factors. This analysis revealed the central role of GC content in mRNA fate, in terms of P-body localization, mRNA translation and mRNA decay. It also rationalized why PBs mRNAs have a strikingly low protein yield. We report too the existence of distinct mRNA decay pathways with preference for AU-rich or GC-rich transcripts. Compared to this impact of the GC content, sequence-specific RBPs and miRNAs appeared to have only modest additional effects on their bulk targets. Altogether, these results lead to an integrated view of post-transcriptional control in human cells where most regulation at the level of translation is dedicated to AU-rich mRNAs, which have a limiting protein yield, whereas regulation at the level of 5' decay applies to GC-rich mRNAs, whose translation is optimal.

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Section: Introductionmentioning

confidence: 99%

GC content shapes mRNA decay and storage in human cells

Courel

Clément

Foretek

et al. 2018

Preprint

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“…Tristetraprolin (TTP, encoded by Ttp, also known as Zfp36) is an RNA-binding and -destabilizing protein that targets preferentially AU-rich elements (AREs) in 3′-UTRs for degradation by recruiting the CCR4-NOT deadenylase and the decapping complex (8). A multifaceted and still incompletely understood regulation of TTP by transcriptional, posttranscriptional, and posttranslational mechanisms orchestrates TTP activity, such that an efficient degradation occurs in the resolution phase of inflammation, and a premature degradation of target mRNAs is avoided (8)(9)(10)(11)(12)(13). Ttp-knockout mice are born healthy but suffer from granulocytic hyperplasia and develop a progressive and eventually lethal pleiotropic inflammation (14).…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

Ebner

Sedlyarov

Tasciyan

et al. 2017

Journal of Clinical Investigation

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“…We have argued previously that TTP family members containing TZF domains of the type we have been discussing, with or without linkage to C‐terminal CNOT1 binding domains, must have been present in a common ancestor of humans and the most primitive plants and protists more than 1.5 billion years ago (Blackshear & Perera, ; Wells et al, ). However, the genes encoding these proteins have continued to evolve.…”

Section: Introductionmentioning

confidence: 95%

“…Members of the tristetraprolin (TTP) family of mRNA binding proteins can bind directly to AU‐rich elements within mRNAs, and then promote decay of those mRNAs and/or inhibit their translation (Brooks & Blackshear, ; Wells, Perera, & Blackshear, ). The earliest example of this activity was seen with mouse TTP, which was found to bind directly to AU‐rich elements within the 3′‐untranslated region (UTR) of the mRNA encoding tumor necrosis factor alpha (TNF), promoting decay of the mRNA and inhibiting production and secretion of the TNF protein, a major pro‐inflammatory cytokine (Carballo, Gilkeson, & Blackshear, ; Carballo, Lai, & Blackshear, ; Taylor et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…We have found members of the TTP family in all four kingdoms of eukarya, using as the defining characteristic the presence of the RNA‐binding tandem zinc finger (TZF) domain (Blackshear & Perera, ; Wells et al, ). We have found that TZF domains from human and very distant organisms, such as lower plants, bind the characteristic RNA binding sites with remarkably similar binding attributes in terms of affinity and target sequence specificity.…”

Section: Introductionmentioning

confidence: 99%

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The tandem zinc finger RNA binding domain of members of the tristetraprolin protein family

et al. 2019

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Tristetraprolin (TTP), the prototype member of the protein family of the same name, was originally discovered as the product of a rapidly inducible gene in mouse cells. Development of a knockout (KO) mouse established that absence of the protein led to a severe inflammatory syndrome, due in part to elevated levels of tumor necrosis factor (TNF). TTP was found to bind directly and with high affinity to specific AU‐rich sequences in the 3′‐untranslated region of the TNF mRNA. This initial binding led to promotion of TNF mRNA decay and inhibition of its translation. Many additional TTP target mRNAs have since been identified, some of which are cytokines and chemokines involved in the inflammatory response. There are three other proteins in the mouse with similar activities and domain structures, but whose KO phenotypes are remarkably different. Moreover, proteins with similar domain structures and activities have been found throughout eukaryotes, demonstrating that this protein family arose from an ancient ancestor. The defining characteristic of this protein family is the tandem zinc finger (TZF) domain, a 64 amino acid sequence with many conserved residues that is responsible for the direct RNA binding. We discuss here many aspects of this protein domain that have been elucidated since the original discovery of TTP, including its sequence conservation throughout eukarya; its apparent continued evolution in some lineages; its functional dependence on many key conserved residues; its “interchangeability” among evolutionarily distant species; and the evidence that RNA binding is required for the physiological functions of the proteins. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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An Ancient Family of RNA-Binding Proteins: Still Important!

Cited by 57 publications

References 70 publications

GC content shapes mRNA decay and storage in human cells

GC content shapes mRNA decay and storage in human cells

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

The tandem zinc finger RNA binding domain of members of the tristetraprolin protein family

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