RESUMEN
Flavaglines are cyclopenta[b]benzofurans found in plants of the genus Aglaia, several species of which are used in traditional Chinese medicine. These compounds target the initiation factor of translation eIF4A and the scaffold proteins prohibitins-1 and 2 (PHB1/2) to exert various pharmacological activities, including antiviral effects against several types of viruses, including coronaviruses. This review is focused on the antiviral effects of flavaglines and their therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Asunto(s)
Aglaia/química , Antivirales/uso terapéutico , Productos Biológicos/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Factor 4A Eucariótico de Iniciación/genética , Neumonía Viral/tratamiento farmacológico , Proteínas Represoras/genética , Animales , COVID-19 , Factor 4A Eucariótico de Iniciación/efectos de los fármacos , Humanos , Medicina Tradicional China , Pandemias , Prohibitinas , Proteínas Represoras/efectos de los fármacosRESUMEN
BACKGROUND: The exon junction complex (EJC), which contains four core components, eukaryotic initiation factor 4AIII (eIF4AIII), MAGO/NASHI (MAGO), Y14/Tsunagi/RNA-binding protein 8A, and Barentsz/Metastatic lymph node 51, is formed in both nucleus and cytoplasm, and plays important roles in gene expression. Genes encoding core EJC components have been found in plants, including rice. Currently, the functional characterizations of MAGO and Y14 homologs have been demonstrated in rice. However, it is still unknown whether eIF4AIII is essential for the functional EJC in rice. RESULTS: This study investigated two DEAD box RNA helicases, OsRH2 and OsRH34, which are homologous to eIF4AIII, in rice. Amino acid sequence analysis indicated that OsRH2 and OsRH34 had 99 % identity and 100 % similarity, and their gene expression patterns were similar in various rice tissues, but the level of OsRH2 mRNA was about 58-fold higher than that of OsRH34 mRNA in seedlings. From bimolecular fluorescence complementation results, OsRH2 and OsRH34 interacted physically with OsMAGO1 and OsY14b, respectively, which indicated that both of OsRH2 and OsRH34 were core components of the EJC in rice. To study the biological roles of OsRH2 and OsRH34 in rice, transgenic rice plants were generated by RNA interference. The phenotypes of three independent OsRH2 and OsRH34 double-knockdown transgenic lines included dwarfism, a short internode distance, reproductive delay, defective embryonic development, and a low seed setting rate. These phenotypes resembled those of mutants with gibberellin-related developmental defects. In addition, the OsRH2 and OsRH34 double-knockdown transgenic lines exhibited the accumulation of unspliced rice UNDEVELOPED TAPETUM 1 mRNA. CONCLUSIONS: Rice contains two eIF4AIII paralogous genes, OsRH2 and OsRH34. The abundance of OsRH2 mRNA was about 58-fold higher than that of OsRH34 mRNA in seedlings, suggesting that the OsRH2 is major eIF4AIII in rice. Both OsRH2 and OsRH34 are core components of the EJC, and participate in regulating of plant height, pollen, and seed development in rice.
Asunto(s)
ARN Helicasas DEAD-box/genética , Factor 4A Eucariótico de Iniciación/genética , Exones/genética , Oryza/genética , Proteínas de Plantas/genética , Secuencia de Aminoácidos , Núcleo Celular/metabolismo , Citoplasma/metabolismo , ARN Helicasas DEAD-box/metabolismo , Factor 4A Eucariótico de Iniciación/clasificación , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Microscopía Fluorescente , Oryza/crecimiento & desarrollo , Oryza/metabolismo , Filogenia , Proteínas de Plantas/clasificación , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente , Polen/genética , Polen/crecimiento & desarrollo , Polen/metabolismo , Unión Proteica , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Semillas/genética , Semillas/crecimiento & desarrollo , Semillas/metabolismo , Homología de Secuencia de AminoácidoRESUMEN
Here Budiman et al. (2009) demonstrate that the selective translation of selenocysteine-containing proteins can be regulated by the mutually exclusive binding of eIF4a3 and SECIS binding protein 2 (SBP2) to a cis-acting element in the 3' untranslated region (3'UTR) of the target mRNA.
Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Factor 4A Eucariótico de Iniciación/metabolismo , Modificación Traduccional de las Proteínas , Proteínas de Unión al ARN/metabolismo , Selenoproteínas/biosíntesis , Regiones no Traducidas 3' , Animales , Sitios de Unión , Codón de Terminación , ARN Helicasas DEAD-box/genética , Inducción Enzimática , Factor 4A Eucariótico de Iniciación/genética , Glutatión Peroxidasa/biosíntesis , Homeostasis , Humanos , Conformación de Ácido Nucleico , Fosfolípido Hidroperóxido Glutatión Peroxidasa , ARN Mensajero/biosíntesis , ARN Mensajero/química , Ratas , Selenio/deficiencia , Selenio/metabolismo , Selenocisteína/metabolismo , Selenoproteínas/genética , Glutatión Peroxidasa GPX1RESUMEN
The synthesis of selenoproteins requires the translational recoding of the UGA stop codon as selenocysteine. During selenium deficiency, there is a hierarchy of selenoprotein expression, with certain selenoproteins synthesized at the expense of others. The mechanism by which the limiting selenocysteine incorporation machinery is preferentially utilized to maintain the expression of essential selenoproteins has not been elucidated. Here we demonstrate that eukaryotic initiation factor 4a3 (eIF4a3) is involved in the translational control of a subset of selenoproteins. The interaction of eIF4a3 with the selenoprotein mRNA prevents the binding of SECIS binding protein 2, which is required for selenocysteine insertion, thereby inhibiting the synthesis of the selenoprotein. Furthermore, the expression of eIF4a3 is regulated in response to selenium. Based on knockdown and overexpression studies, eIF4a3 is necessary and sufficient to mediate selective translational repression in cells. Our results support a model in which eIF4a3 links selenium status with differential selenoprotein expression.
Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Factor 4A Eucariótico de Iniciación/metabolismo , Modificación Traduccional de las Proteínas , Proteínas de Unión al ARN/metabolismo , Selenio/metabolismo , Selenocisteína/metabolismo , Selenoproteínas/biosíntesis , Regiones no Traducidas 3' , Animales , Sitios de Unión , Línea Celular Tumoral , Codón de Terminación , ARN Helicasas DEAD-box/genética , Inducción Enzimática , Factor 4A Eucariótico de Iniciación/genética , Glutatión Peroxidasa/biosíntesis , Homeostasis , Peso Molecular , Conformación de Ácido Nucleico , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Mensajero/química , Ratas , Selenio/deficiencia , Proteínas de Unión al Selenio/metabolismo , Selenoproteínas/genética , Transfección , Glutatión Peroxidasa GPX1Asunto(s)
Factor 4A Eucariótico de Iniciación/genética , Factor 4A Eucariótico de Iniciación/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Esteroles/farmacología , Adenosina Trifosfato/química , Animales , Antozoos/metabolismo , Humanos , Modelos Biológicos , Iniciación de la Cadena Peptídica Traduccional , Extractos Vegetales/química , Extractos Vegetales/farmacología , Estructura Secundaria de Proteína , ARN Mensajero/metabolismo , Esteroles/químicaRESUMEN
Chronic skin disorders that require long-term treatment with corticosteroids, such as vitiligo, may use a combination of topical corticosteroids and topical all-trans-retinoic acid (ATRA) to prevent corticosteroid-induced skin atrophy. Besides protecting against the side effects of corticosteroids, ATRA produces a better clinical outcome in some patients. This study examined whether ATRA influences the expression of mRNAs responsible for the clinical correlation. Differential display was performed using kits incorporating an annealing control primer. Epidermis from suction blisters taken from six patients diagnosed with a generalized type of vitiligo, who were included in a placebo-controlled paired-comparison left-right study using ATRA and vehicle for 3-6 months, were used. Ten differentially expressed mRNAs were identified in those six patients. Expression levels were restored to normal particularly in four types of mRNAs, which were matched with sequences encoding eukaryotic translation initiation factor 4A1 (eIF4A1), ribosomal protein L13, mediator of RNA polymerase to transcription (MRT) and ribosomal phosphoprotein PO. Of those mRNAs, the level of eIF4A1 mRNA showed a clinical correlation; The expression of eIF4A1 mRNA, examined by real-time PCR, was elevated in four patients who showed a favorable clinical response to ATRA, whereas no change or a decrease occurred in three patients whose clinical responses did not differ between ATRA and vehicle treatment. The eIF4A1 protein expression from the other two patients, one of them with a favorable response to ATRA, also showed a clinical correlation. Therefore, eIF4A1 mRNA may be an important gene related to ATRA effects, although further studies are required.