Translon: a single term for translated regions.
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Letter↗
Biomedical subjects
Nicola K Gray
Publications and source records attributed to Nicola K Gray.
Cleavage, a real turn-off? HIV-mediated proteolysis of PABP1.
In this issue of the Biochemical Journal, Alvarez and colleagues have identified PABP1 [poly(A)-binding protein 1] as a target of protease cleavage during HIV infection. The study shows that HIV-1, HIV-2 and mouse mammary tumour virus, but not other retroviruses, target PABP1 for cleavage and identifies cleavage sites within the RNA-recognition motifs and C-terminal region of the protein. This suggests that PABP1 cleavage may be important in the shut-off of host translation during HIV infection. This extends the viral families that are known to target PABP1 to include Retroviridae, suggesting that PABP1 may be a central target of viral infection.
Animals↗
Direct stimulation of translation by the multifunctional herpesvirus ICP27 protein.
Herpes simplex virus type 1 (HSV-1) ICP27 protein is an essential regulator of viral gene expression with roles at various levels of RNA metabolism in the nucleus. Using the tethered function assay, we showed a cytoplasmic activity for ICP27 in directly enhancing mRNA translation in vivo in the absence of other viral factors. The region of ICP27 required for translational stimulation maps to the C terminus. Furthermore, in infected cells, ICP27 is associated with polyribosomes, indicating a function in translation during the lytic cycle.
Animals↗
Dazl binds in vivo to specific transcripts and can regulate the pre-meiotic translation of Mvh in germ cells.
Gametogenesis is a complex process subject to strict controls at both levels of transcription and translation. Members of a family of conserved RNA-binding proteins encoded by the DAZ genes are required for the translational regulation of gene expression essential for this process. Although loss of DAZ family genes is associated with infertility in several organisms including humans, the identity of the transcripts regulated in vivo is unknown. Using a combination of immunoprecipitation and microarray analysis, we have identified a number of mRNAs that are bound by the murine Dazl protein both in vivo and in vitro. Sequence analysis shows that these transcripts contain binding sites for Dazl, which have been conserved during evolution between human, rat and mouse. We have focussed on mouse vasa homologue (Mvh), a gene that is essential for male gametogenesis, and show that Dazl stimulates translation via the Mvh 3'-UTR. Finally, we show that germ cells of Dazl null mice contain reduced levels of Mvh protein, indicating that Dazl-mediated regulation of Mvh translation is crucial for mammalian spermatogenesis.
3' Untranslated Regions↗
The DAZL family proteins are PABP-binding proteins that regulate translation in germ cells.
DAZL proteins are germ-cell-specific RNA-binding proteins essential for gametogenesis. The precise molecular role of these proteins in germ-cell development remains enigmatic; however, they appear to function in the cytoplasm. In order to directly address the function of vertebrate DAZL proteins, we have used Xenopus laevis oocytes as a model system. Here we demonstrate that members of this family, including Xdazl, mouse Dazl, human DAZL, human DAZ and human BOULE, have the ability to stimulate translation and function at the level of translation initiation. We show that DAZL proteins interact with poly(A)-binding proteins (PABPs), which are critical for the initiation of translation. Mapping and tethered function experiments suggest that these interactions are physiologically important. This leads to an attractive hypothesis whereby DAZL proteins activate translationally silent mRNAs during germ cell development through the direct recruitment of PABPs.
Adenosine↗
Embryonic poly(A)-binding protein stimulates translation in germ cells.
The function of poly(A)-binding protein 1 (PABP1) in poly(A)-mediated translation has been extensively characterized. Recently, Xenopus laevis oocytes and early embryos were shown to contain a novel poly(A)-binding protein, ePABP, which has not been described in other organisms. ePABP was identified as a protein that binds AU-rich sequences and prevents shortening of poly(A) tails. Here, we show that ePABP is also expressed in X. laevis testis, suggesting a more general role for ePABP in gametogenesis. We find that ePABP is conserved throughout vertebrates and that mouse and X. laevis cells have similar tissue-specific ePABP expression patterns. Furthermore, we directly assess the role of ePABP in translation. We show that ePABP is associated with polysomes and can activate the translation of reporter mRNAs in vivo. Despite its relative divergence from PABP1, we find that ePABP has similar functional domains and can bind to several PABP1 partners, suggesting that they may use similar mechanisms to activate translation. In addition, we find that PABP1 and ePABP can interact, suggesting that these proteins may be bound simultaneously to the same mRNA. Finally, we show that the activity of both PABP1 and ePABP increases during oocyte maturation, when many mRNAs undergo polyadenylation.
Amino Acid Sequence↗
The stem-loop binding protein stimulates histone translation at an early step in the initiation pathway.
Metazoan replication-dependent histone mRNAs do not have a poly(A) tail but end instead in a conserved stem-loop structure. Efficient translation of these mRNAs is dependent on the stem-loop binding protein (SLBP). Here we explore the mechanism by which SLBP stimulates translation in vertebrate cells, using the tethered function assay and analyzing protein-protein interactions. We show for the first time that translational stimulation by SLBP increases during oocyte maturation and that SLBP stimulates translation at the level of initiation. We demonstrate that SLBP can interact directly with subunit h of eIF3 and with Paip1; however, neither of these interactions is sufficient to mediate its effects on translation. We find that Xenopus SLBP1 functions primarily at an early stage in the cap-dependent initiation pathway, targeting small ribosomal subunit recruitment. Analysis of IRES-driven translation in Xenopus oocytes suggests that SLBP activity requires eIF4E. We propose a model in which a novel factor contacts eIF4E bound to the 5' cap and SLBP bound to the 3' end simultaneously, mediating formation of an alternative end-to-end complex.
5' Untranslated Regions↗
A novel role for shuttling SR proteins in mRNA translation.
The Ser-Arg-rich (SR) proteins comprise a large family of nuclear phosphoproteins that are required for constitutive and alternative splicing. A subset of SR proteins shuttles continuously between the nucleus and the cytoplasm, suggesting that the role of shuttling SR proteins in gene expression may not be limited to nuclear pre-mRNA splicing, but may also include unknown cytoplasmic functions. Here, we show that shuttling SR proteins, in particular SF2/ASF, associate with translating ribosomes and stimulate translation when tethered to a reporter mRNA in Xenopus oocytes. Moreover, SF2/ASF enhances translation of reporter mRNAs in HeLa cells, and this activity is dependent on its ability to shuttle from the nucleus to the cytoplasm and is increased by the presence of an exonic-splicing enhancer. Furthermore, SF2/ASF can stimulate translation in vitro using a HeLa cell-free translation system. Thus, the association of SR proteins with translating ribosomes, as well as the stimulation of translation both in vivo and in vitro, strongly suggest a role for shuttling SR proteins in translation. We propose that shuttling SR proteins play multiple roles in the posttranscriptional expression of eukaryotic genes and illustrate how they may couple splicing and translation.
Active Transport, Cell Nucleus↗
The roles of cytoplasmic poly(A)-binding proteins in regulating gene expression: a developmental perspective.
Poly(A)-binding proteins (PABPs) are central to the regulation of messenger RNA (mRNA) translation and stability; however, the roles and contributions of different PABP family members in controlling gene expression are not yet fully understood. In this paper, the current state of knowledge of the different cytoplasmic PABP proteins and their function in animal cells will be summarised, with particular reference to their roles in development. Possible regulatory mechanisms and potential new roles for these proteins in the control of specific mRNAs are also highlighted.
Animals↗
Regulation of mRNA translation by 5'- and 3'-UTR-binding factors.
The translational regulation of specific mRNAs is important for controlling gene expression. The past few years have seen a rapid expansion in the identification and characterization of mRNA regulatory elements and their binding proteins. For the majority of these examples, the mechanism by which translational regulation is achieved is not well understood. Nevertheless, detailed analyses of a few examples show that almost every event in the initiation pathway, from binding of the cap complex to the joining of the 60S ribosomal subunit, is subject to regulation.
3' Untranslated Regions↗