English

Abstract

Introduction Organisms are able to generate organised responses to environmental changes by controlling the level of messenger RNA translation. The ability to respond rapidly allows the mobilization of the host’s defences and coordination of innate response to different infections. A large number of microbial pathogens inhibit the translation of host cells. Bacterial and virus infections interfere with protein synthesis of the host and activating or suppressing the innate responses, thus manipulating the translational machinery. Mortality, morbidity and economic adverse effects associated with fungal infections along with the emergence of resistance to antifungal agents make it necessary to gain a better understanding of the pathogenesis and discovery of new agents for treatment of those infections. There is little knowledge regarding the role of translational regulation in fungus–host relationship. The present review aims to show how translation regulation occurs in bacteria and virus infections and shows a mysterious role of translational regulation in the context of fungal infections. Conclusion In the last few years, incidence of fungal diseases has dramatically increased especially in immunodepressed individuals, representing a serious health problem since these diseases are associated with high mortality. There is a growing list of reports describing antifungal resistance in clinical isolates. Considering these facts, it is necessary for a better understanding of the pathophysiology of fungal infections that may reveal new therapeutic targets. Introduction The regulated translation of mRNAs in eukaryotes is a powerful tool of posttranscriptional control of gene expression. Translation has a fundamental role in cell growth and differentiation, development, learning, memory and synaptic plasticity. This process and its regulation have a relevant role in infections and host defence, allowing quick responses to contain pathogenic microorganisms. Regulation of these events occurs primarily at the steps of initiation and elongation. Figure 1 resumes the process. Before mRNA decoding, the eukaryotic 40S ribosomal subunit forms a 43S pre-initiation complex composed of different eukaryotic translation initiation factors (eIFs) and initiator tRNA charged with methionine (Met-tRNAi—see Figure 1). This association involves elF2, a heterotrimer that forms an active ternary complex (TC) containing GTP and aminoacylated initiator tRNA. In the presence of eIF4F complex, TC carries Met-tRNAi to 40S ribosome, a fundamental step to start protein synthesis at AUG codon or cognates1. eIF4F binds to the cap structure present in the 5 -end of eukaryotic mRNAs. This interaction promotes correct positioning of ribosome relative to mRNA, thus facilitating the ATP-dependent movement of it that is named as ‘scanning’ and locates the translation initiation codon AUG2. eIF4F is composed of a cap-binding protein (eIF4E), an RNA helicase (eIF4A) and a scavenger protein (eIF4G). eIF4E binds to the cap while eIF4G associates with eIF3 linked to a ribosome, allowing correct positioning of 43S complex at the mRNA 5 -end. Besides, eIF4E binds to PABP (poly(A)-binding protein) connecting 5 and 3 -ends of mRNAs, resulting in mRNA circularization that is supposed to be important for a rapid turnover in protein synthesis1. Translation initiation is the limiting step of protein synthesis in most circumstances, and then the process is subject to elegant regulatory mechanisms1. Initiation step is regulated by the availability of eIF4F2. The binding of eIF4E to eIF4G is modulated by a serine/threonine kinase, TOR1, which responds to growth factors, nutrients, amino acids, oxygen and energy availability3. In this context, TOR1 in a TORC1 complex, which controls eIF4E activity through phosphorylation of 4E-BPs (eIF4Ebinding proteins). Hyperphosphorylated 4E-BPs interact with eIF4E, preventing the formation of eIF4F complex and thus suppressing the cap-dependent translation, while hypophosphorylation of these proteins by mTORC1 promotes the release of eIF4E-eIF4G binding, stimulating the cap-dependent translation. After AUG initiation codon recognition, eIF5 stimulates the hydrolysis of GTP bound to eIF21. In a reaction catalysed by eIF5B, the 40S ribosomal subunit binds to 60S and * Corresponding author Email: gouveia_va@yahoo.com; gouveiava@ ufmg.br Laboratorio de Biologia Celular de Microrganismos, Departamento de Microbiologia – ICB, Universidade Federal de Minas Gerais, Brazil