mRNA Targeting, Transport and Local Translation in Eukaryotic Cells: From the Classical View to a Diversity of New Concepts

Abstract

Spatial organization of protein biosynthesis in the eukaryotic cell has been studied for more than fifty years, thus many facts have already been included in textbooks. According to the classical view, mRNA transcripts encoding secreted and transmembrane proteins are translated by ribosomes associated with endoplasmic reticulum membranes, while soluble cytoplasmic proteins are synthesized on free polysomes. However, in the last few years, new data has emerged, revealing selective translation of mRNA on mitochondria and plastids, in proximity to peroxisomes and endosomes, in various granules and at the cytoskeleton (actin network, vimentin intermediate filaments, microtubules and centrosomes). There are also long-standing debates about the possibility of protein synthesis in the nucleus. Localized translation can be determined by targeting signals in the synthesized protein, nucleotide sequences in the mRNA itself, or both. With RNA-binding proteins, many transcripts can be assembled into specific RNA condensates and form RNP particles, which may be transported by molecular motors to the sites of active translation, form granules and provoke liquid-liquid phase separation in the cytoplasm, both under normal conditions and during cell stress. The translation of some mRNAs occurs in specialized “translation factories,” assemblysomes, transperons and other structures necessary for the correct folding of proteins, interaction with functional partners and formation of oligomeric complexes. Intracellular localization of mRNA has a significant impact on the efficiency of its translation and presumably determines its response to cellular stress. Compartmentalization of mRNAs and the translation machinery also plays an important role in viral infections. Many viruses provoke the formation of specific intracellular structures, virus factories, for the production of their proteins. Here we review the current concepts of the molecular mechanisms of transport, selective localization and local translation of cellular and viral mRNAs, their effects on protein targeting and topogenesis, and on the regulation of protein biosynthesis in different compartments of the eukaryotic cell. Special attention is paid to new systems biology approaches, providing new cues to the study of localized translation.

Understanding circadian regulation of mammalian cell function, protein homeostasis, and metabolism

“…We have described how several rhythmic cellular functions may simply result from the direct or indirect consequences of mTORC-mediated daily rhythms in the global translation rate and associated changes in cytosolic protein levels, crowding, metabolism and ion transport. Returning to our initial examples, phagocytosis and motility are reliant on actin dynamics, which are mTORC2-regulated and accelerated by crowding [ 80 , 81 ], flux through the secretory pathway is sensitive to global translation rate [ 86 ], and rhythms in cardiomyocyte electrical activity result from osmotic buffering of cytosolic protein levels [ 7 ]. Only in the final case was the mTORC dependence of rhythmic cell function tested, with modest TORC inhibition abolishing daily firing rate oscillations in cultured cardiomyocytes, as well as circadian variation in heart rate ex vivo and in vivo (under autonomic blockade).…”

Subcellular Localization of Fad1p in Saccharomyces cerevisiae: A Choice at Post-Transcriptional Level?

“…All together, these data suggest the existence of a fine mechanism regulating the localization of the natural Fad1p, presumably at the transcript level and dependent on the carbon source. It is well-established that intracellular localization of mRNA has a significant impact on the efficiency of its translation and, presumably, determines its response to changing metabolic conditions or cellular stress [72].…”

Non-Canonical Translation Initiation Mechanisms Employed by Eukaryotic Viral mRNAs

“…Compartmentalized translation of viral mRNAs. Mechanisms associated with localized translation, formation of RNP granules, and generation of viral compartments within the cell deserve separate consideration [ 258 ]. In many RNA viruses, the life cycle is based on the formation of specialized “viral factories” (VFs) – intracellular structures made up of the membrane-bound organelles of the cell [ 259 ].…”

“…As a rule, VFs in (+)RNA-containing viruses serve exclusively as platforms for the synthesis of viral RNA, while in a number of viruses with dsRNA and (-)RNA genomes, they are also involved in the translation of their mRNA, protecting them from the action of cellular regulatory mechanisms. Viruses can actively recruit translational factors into such specialized compartments [ 258 ]. Association of viral mRNA translation with membranes could play a role in its resistance to the cellular response to infection even without regard to VF.…”

“…However, many viruses skillfully manipulate this process, either by preventing granule formation (for example, by proteolysis of their key components), as do ZIKV, VSV, IAV, and a number of picornaviruses, or, conversely, facilitating their assembly at an advantageous time in their life cycle, like RuV [ 260 , 261 ]. More details about the mechanisms associated with localized translation of viral mRNA and manipulation with the membrane and granular compartments can be found in the relevant reviews [ 258 - 261 ].…”