Protein synthesis in health and disease: editorial

Abstract

The process of protein synthesis (mRNA translation) is essential for the growth and survival of all living organisms. Protein synthesis places heavy demands upon the cell—it requires a supply of amino acids as precursors and a great deal of energy. For these reasons, overall protein synthesis is under tight control. Furthermore, the translation of specific mRNAs is also subject to sophisticated control mechanisms, allowing the cell to modulate the production of certain proteins. Regulating translation rather than earlier stages in gene expression (transcription, splicing) confers important advantages—especially rapidity (by avoiding the requirement for de novo transcription and mRNA processing) and spatial control, e.g., in early development. Great strides have now been made in understanding how protein synthesis works and the functions and structures of the components involved. The chapters in this volume broadly concern two different areas of translational control. The first four primarily concern the regulation of the protein factors involved in the process of translation. This regulation generally involves alterations in their states of phosphorylation which influence their activity and interactions. The chapter by Proud describes the control of eukaryotic initiation factor 2. Its control has been intensively studied as it was a very early example of regulation of translation by protein phosphorylation. It is a target for four mammalian protein kinases which play important roles in regulating translation in response to diverse stress conditions. Recent data, using knock-in or knock-out mouse models, have clearly shown the importance of the kinases for normal physiology. It is also now clear that inherited mutations either in one of these kinases or in an ancillary factor for eIF2 (eIF2B) can lead to severe human diseases, as also discussed by Proud. Clemens discusses the mechanisms by which viruses seek to subvert the cellular protein synthesis machinery to favour expression of their own genetic information and the ways in which host cells strive to prevent this. A key player here is an eIF2 kinase termed PKR. Many of the mechanisms are also relevant in uninfected cells in response to stresses or early in apoptosis. As precursors for protein synthesis, amino acids exert important regulatory effects on the translational machinery. Some are exerted through eIF2, others through a key signaling pathway involving a protein termed the mammalian target of rapamycin, mTOR. Kimball focuses on recent studies that employ intact animals, rather than isolated cells, to explore the roles of amino acids in regulating translation factor activity. The mTOR pathway is currently the focus of intense attention. This reflects both its key roles in cellular and organismal physiology, and the links between this pathway and a range of human diseases including certain types of cancer and a condition termed tuberous sclerosis. Tee and Blenis discuss how studies on tuberous sclerosis have led to an improved understanding of mTOR signaling, and the roles of mTOR in health and disease. The second group of articles concern features of mRNA molecules themselves that are important for the control of their translation. In many cases, these features lie in the 5?- or 3?-untranslated regions (UTRs) of the message. Pickering and Willis review the roles of elements in the 5?-UTRs of certain mRNAs in mediating or controlling their translation. These include internal ribosome entry sites, which were initially found in viral mRNAs and which allow these mRNAs to be efficiently translated in the host cell. The articles by de Moor and colleagues and by Espel concern features found in the 3?-UTRs of specific mRNAs. The first chapter discusses 3?-UTR elements that are important in controlling the translation of specific mRNAs during early development and cell differentiation and during the cell cycle. The resulting translational control processes play critical roles in a diverse array of biological processes. A range of such regulatory elements have been identified, and these work by interacting with specific RNA-binding proteins. This is also true of the distinct 3?-UTR elements described by Espel: these AU-rich elements (AREs) play important roles in regulating the stability and translation of mRNAs encoding pro-inflammatory proteins and tumour-related proteins. As discussed by Espel, particular attention has focused on the role of AREs and ARE-binding proteins in inflammation, and on the signaling pathways involved. As the reader will appreciate from this set of articles, it is now abundantly clear that translational control is crucial for normal development and growth, and that dysregulation of these mechanisms leads to a range of serious human diseases.