Eukaryotic translation initiation factor eIF4E-5 is required for spermiogenesis in Drosophila melanogaster.

Drosophila sperm development is characterized by extensive post-transcriptional regulation whereby thousands of transcripts are preserved for translation during later stages. A key step in translation initiation is the binding of eukaryotic initiation factor 4E (eIF4E) to the 5' mRNA cap. In addition to canonical eIF4E-1, Drosophila has multiple eIF4E paralogs, including four (eIF4E-3, -4, -5, and -7) that are highly expressed in the testis. Among these, only eIF4E-3 has been characterized genetically. Here, using CRISPR/Cas9 mutagenesis, we determined that eIF4E-5 is essential for male fertility. eIF4E-5 protein localizes to the distal ends of elongated spermatid cysts, and eIF4E-5 mutants exhibit defects during post-meiotic stages, including a mild defect in spermatid cyst polarization. eIF4E-5 mutants also have a fully penetrant defect in individualization, resulting in failure to produce mature sperm. Indeed, our data indicate that eIF4E-5 regulates non-apoptotic caspase activity during individualization by promoting local accumulation of the E3 ubiquitin ligase inhibitor Soti. Our results further extend the diversity of non-canonical eIF4Es that carry out distinct spatiotemporal roles during spermatogenesis.

Female meiosis II and pronuclear fusion require the microtubule transport factor Bicaudal D.

Bicaudal D (BicD) is a dynein adaptor that transports different cargoes along microtubules. Reducing the activity of BicD specifically in freshly laid Drosophila eggs by acute protein degradation revealed that BicD is needed to produce normal female meiosis II products, to prevent female meiotic products from re-entering the cell cycle, and for pronuclear fusion. Given that BicD is required to localize the spindle assembly checkpoint (SAC) components Mad2 and BubR1 to the female meiotic products, it appears that BicD functions to localize these components to control metaphase arrest of polar bodies. BicD interacts with Clathrin heavy chain (Chc), and both proteins localize to centrosomes, mitotic spindles and the tandem spindles during female meiosis II. Furthermore, BicD is required to localize clathrin and the microtubule-stabilizing factors transforming acidic coiled-coil protein (D-TACC/Tacc) and Mini spindles (Msps) correctly to the meiosis II spindles, suggesting that failure to localize these proteins may perturb SAC function. Furthermore, immediately after the establishment of the female pronucleus, D-TACC and Caenorhabditis elegans BicD, tacc and Chc are also needed for pronuclear fusion, suggesting that the underlying mechanism might be more widely used across species.

High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors.

Cervical cancer is the fourth most common cause of cancer in women worldwide in terms of both incidence and mortality. Persistent infection with high-risk types of human papillomavirus (HPV), namely 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, constitute a necessary cause for the development of cervical cancer. Viral oncoproteins E6 and E7 play central roles in the carcinogenic process by virtue of their interactions with cell master proteins such as p53, retinoblastoma (Rb), mammalian target of rapamycin (mTOR), and c-MYC. For the synthesis of E6 and E7, HPVs use a bicistronic messenger RNA (mRNA) that has been studied in cultured cells. Here, we report that in cervical tumors, HPV-18, -39, and -45 transcribe E6/E7 mRNAs with extremely short 5' untranslated regions (UTRs) or even lacking a 5' UTR (i.e., zero to three nucleotides long) to express E6. We show that the translation of HPV-18 E6 cistron is regulated by the motif ACCaugGCGCG(C/A)UUU surrounding the AUG start codon, which we term Translation Initiation of Leaderless mRNAs (TILM). This motif is conserved in all HPV types of the phylogenetically coherent group forming genus alpha, species 7, which infect mucosal epithelia. We further show that the translation of HPV-18 E6 largely relies on the cap structure and eIF4E and eIF4AI, two key translation initiation factors linking translation and cancer but does not involve scanning. Our results support the notion that E6 forms the center of the positive oncogenic feedback loop node involving eIF4E, the mTOR cascade, and p53.

Palm density and grazing effects on plant communities: implications for livestock management in a Butia palm grove.

Some grasslands in ecotones with forests tend to be encroached by woody species, because of changes in climate and land use. Such structural changes in vegetation can be facilitated when the grassland community presents an autochthonous arboreal component, like Butia palms. We aim to identify the responses of taxonomic and functional diversity on grassland community with the occurrence of arborescent/arboreal species (autochthonous and encroaching) to palm density and grazing intensity. The study was conducted in a Butia odorata palm grove under cattle management, in Southern Brazil. To assess the taxonomic and functional composition we performed ordinations analysis with the vegetational data and using path analysis we assessed the causal relationships between variables of interest. Density of Butia odorata and woody plants were strongly positive related, suggesting a facilitation process in the establishment of arborescent plants on the grassland matrix. The abundance of less palatable plants and grazing pressure were inversely related, indicating a selection process induced by higher grazing intensity. We suggest that the grazing intensity management must be based on the autochthonous tree density, applying higher grazing intensity in areas with higher density of encroaching plants, in addition to maintaining other regions conducive to Butia palm regeneration through fallows.

Translational control in the naked mole-rat as a model highly resistant to cancer.

Dysregulation of mRNA translation is involved in the onset and progression of different types of cancer. To gain insight into novel genetic strategies to avoid this malady, we reviewed the available genomic, transcriptomic, and proteomic data about the translational machinery from the naked-mole rat (NMR) Heterocephalus glaber, a new model of study that exhibits high resistance to cancer. The principal features that might confer cancer resistance are 28S rRNA fragmentation, RPL26 and eIF4G overexpression, global downregulation of mTOR pathway, specific amino acid residues in RAPTOR (P908) and RICTOR (V1695), and the absence of 4E-BP3. These features are not only associated with cancer but also might couple longevity and adaptation to hypoxia. We propose that the regulation of translation is among the strategies endowing NMR cancer resistance.

Autophagy Regulation by the Translation Machinery and Its Implications in Cancer.

Various metabolic pathways and molecular processes in the cell act intertwined, and dysregulating the interplay between some of them may lead to cancer. It is only recently that defects in the translation process, i.e., the synthesis of proteins by the ribosome using a messenger (m)RNA as a template and translation factors, have begun to gain strong attention as a cause of autophagy dysregulation with effects in different maladies, including cancer. Autophagy is an evolutionarily conserved catabolic process that degrades cytoplasmic elements in lysosomes. It maintains cellular homeostasis and preserves cell viability under various stress conditions, which is crucial for all eukaryotic cells. In this review, we discuss recent advances shedding light on the crosstalk between the translation and the autophagy machineries and its impact on tumorigenesis. We also summarize how this interaction is being the target for novel therapies to treat cancer.