Abstract
The canonical molecular machinery required for global mRNA translation and its control has been well defined, with distinct sets of proteins involved in the processes of translation initiation, elongation and termination. Additionally, noncanonical, trans‐acting regulatory RNA‐binding proteins (RBPs) are necessary to provide mRNA‐specific translation, and these interact with 5′ and 3′ untranslated regions and coding regions of mRNA to regulate ribosome recruitment and transit. Recently it has also been demonstrated that trans‐acting ribosomal proteins direct the translation of specific mRNAs. Importantly, it has been shown that subsets of RBPs often work in concert, forming distinct regulatory complexes upon different cellular perturbation, creating an RBP combinatorial code, which through the translation of specific subsets of mRNAs, dictate cell fate. With the development of new methodologies, a plethora of novel RNA binding proteins have recently been identified, although the function of many of these proteins within mRNA translation is unknown. In this review we will discuss these methodologies and their shortcomings when applied to the study of translation, which need to be addressed to enable a better understanding of trans‐acting translational regulatory proteins. Moreover, we discuss the protein domains that are responsible for RNA binding as well as the RNA motifs to which they bind, and the role of trans‐acting ribosomal proteins in directing the translation of specific mRNAs.This article is categorized under: 1RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes2Translation > Translation Regulation3Translation > Translation Mechanisms
Highlights
The process of cap-dependent translation can be divided into three central events: initiation, where eukaryotic initiation factors assemble an elongation competent ribosome at the start codon (Hinnebusch, 2014); elongation, where the ribosome and eukaryotic elongation factors decode the mRNA into a polypeptide (Hershey, 1991); termination, in which the ribosome disassembles after encountering a stop codon and releases the nascent polypeptide, a process that is aided by eukaryotic release factors
It has been shown that individual RNA binding proteins (RBPs) are able to coordinate the translation or repression of specific mRNAs by interacting with defined motifs/structural elements in 50 and 30 untranslated regions (UTRs), or coding regions, and direct cytoplasmic gene expression programs that are required to respond to changes in external conditions
While there are some very well studied examples of trans-acting proteins, including several ribosomal proteins, many novel RBPs have emerged as new regulatory candidates
Summary
The process of cap-dependent translation can be divided into three central events: initiation, where eukaryotic initiation factors (eIFs) assemble an elongation competent ribosome at the start codon (Hinnebusch, 2014); elongation, where the ribosome and eukaryotic elongation factors (eEFs) decode the mRNA into a polypeptide (Hershey, 1991); termination, in which the ribosome disassembles after encountering a stop codon and releases the nascent polypeptide, a process that is aided by eukaryotic release factors (eRFs; Jackson, Hellen, & Pestova, 2012). Bioavailability of eIFs and eEFs through phosphorylation (Hinnebusch, 2014) and in some cases, their cleavage (Bushell et al, 2006) Such changes to the canonical machinery occur under conditions of pathophysiological stress including viral infection, changes in ambient temperatures, cell starvation and hypoxia; allowing reprogramming of the translatome to direct cell fate (Spriggs, Bushell, & Willis, 2010). In addition to control by the canonical translational machinery (Hinnebusch, 2014), numerous RNA binding proteins (RBPs) behave as trans-acting regulatory factors, which either repress or stimulate the translation of specific subsets of mRNAs. It has been shown that individual RBPs are able to coordinate the translation or repression of specific mRNAs by interacting with defined motifs/structural elements in 50 and 30 untranslated regions (UTRs), or coding regions, and direct cytoplasmic gene expression programs that are required to respond to changes in external conditions. We describe four representative RBPs that stimulate and repress the translation of subsets of mRNAs, and discuss the role of trans-acting ribosomal proteins in directing the translation of specific mRNAs
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