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• W2018404810 abstract "The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function. The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function. Many cellular proteins become localized to specific subcellular locations. Spatial localization enables functional compartmentalization and is important for many aspects of cell signaling and behavior. The most common mechanism for protein localization involves direct targeting of the protein itself via specific sequences such as the nuclear or mitochondrial localization sequences (Imai and Nakai, 2010Imai K. Nakai K. Prediction of subcellular locations of proteins: where to proceed?.Proteomics. 2010; 10: 3970-3983Crossref PubMed Scopus (0) Google Scholar). However, a large-scale in situ hybridization study in Drosophila embryogenesis revealed, surprisingly, that 71% of mRNAs of the genes examined (20% of total genes) localize to distinct subcellular compartments where, in many cases, they colocalize with the proteins they encode (Lécuyer et al., 2007Lécuyer E. Yoshida H. Parthasarathy N. Alm C. Babak T. Cerovina T. Hughes T.R. Tomancak P. Krause H.M. Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function.Cell. 2007; 131: 174-187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). This remarkable finding hints at the prevalence of an alternative mechanism for protein localization: subcellular targeting of the mRNA encoding a protein and its subsequent on-site translation. This RNA-based mechanism, the focus of the current review, involves the coordination of multiple complex processes, including mRNA transport, targeting, and translation, and enables remarkably precise stimulus-driven control over protein position, abundance, and, to some extent, function. Subcellular RNA localization is highly prevalent in eukaryotes, ranging from yeast (Gonsalvez et al., 2005Gonsalvez G.B. Urbinati C.R. Long R.M. RNA localization in yeast: moving towards a mechanism.Biol. Cell. 2005; 97: 75-86Crossref PubMed Scopus (0) Google Scholar) to highly specialized cells such as neurons (Bramham and Wells, 2007Bramham C.R. Wells D.G. Dendritic mRNA: transport, translation and function.Nat. Rev. Neurosci. 2007; 8: 776-789Crossref PubMed Scopus (311) Google Scholar, Jung et al., 2012Jung H. Yoon B.C. Holt C.E. Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair.Nat. Rev. Neurosci. 2012; 13: 308-324Crossref PubMed Scopus (3) Google Scholar, Sutton and Schuman, 2006Sutton M.A. Schuman E.M. Dendritic protein synthesis, synaptic plasticity, and memory.Cell. 2006; 127: 49-58Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) and oligodendrocytes (Hoek et al., 1998Hoek K.S. Kidd G.J. Carson J.H. Smith R. hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA.Biochemistry. 1998; 37: 7021-7029Crossref PubMed Scopus (0) Google Scholar), and it is also found in bacteria (Keiler, 2011Keiler K.C. RNA localization in bacteria.Curr. Opin. Microbiol. 2011; 14: 155-159Crossref PubMed Scopus (0) Google Scholar). Neurons serve as an excellent model to understand RNA localization as they are highly polarized: the distal tip of the neuronal axon is remote from its cell body, sometimes a meter away, and therefore can be easily isolated (Campenot and Eng, 2000Campenot R.B. Eng H. Protein synthesis in axons and its possible functions.J. Neurocytol. 2000; 29: 793-798Crossref PubMed Scopus (0) Google Scholar, Taylor et al., 2009Taylor A.M. Berchtold N.C. Perreau V.M. Tu C.H. Li Jeon N. Cotman C.W. Axonal mRNA in uninjured and regenerating cortical mammalian axons.J. Neurosci. 2009; 29: 4697-4707Crossref PubMed Scopus (163) Google Scholar, Zivraj et al., 2010Zivraj K.H. Tung Y.C. Piper M. Gumy L. Fawcett J.W. Yeo G.S. Holt C.E. Subcellular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs.J. Neurosci. 2010; 30: 15464-15478Crossref PubMed Scopus (0) Google Scholar). Comparative subcellular transcriptome analyses in neuronal processes have revealed that distinct sets of mRNAs are targeted to different compartments (Andreassi et al., 2010Andreassi C. Zimmermann C. Mitter R. Fusco S. De Vita S. Saiardi A. Riccio A. An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons.Nat. Neurosci. 2010; 13: 291-301Crossref PubMed Scopus (79) Google Scholar, Cajigas et al., 2012Cajigas I.J. Tushev G. Will T.J. tom Dieck S. Fuerst N. Schuman E.M. The local transcriptome in the synaptic neuropil revealed by deep sequencing and high-resolution imaging.Neuron. 2012; 74: 453-466Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, Gumy et al., 2011Gumy L.F. Yeo G.S. Tung Y.C. Zivraj K.H. Willis D. Coppola G. Lam B.Y. Twiss J.L. Holt C.E. Fawcett J.W. Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization.RNA. 2011; 17: 85-98Crossref PubMed Scopus (0) Google Scholar, Minis et al., 2014Minis A. Dahary D. Manor O. Leshkowitz D. Pilpel Y. Yaron A. Subcellular transcriptomics-Dissection of the mRNA composition in the axonal compartment of sensory neurons.Dev. Neurobiol. 2014; 74: 365-381Crossref PubMed Scopus (0) Google Scholar, Taylor et al., 2009Taylor A.M. Berchtold N.C. Perreau V.M. Tu C.H. Li Jeon N. Cotman C.W. Axonal mRNA in uninjured and regenerating cortical mammalian axons.J. Neurosci. 2009; 29: 4697-4707Crossref PubMed Scopus (163) Google Scholar, Zivraj et al., 2010Zivraj K.H. Tung Y.C. Piper M. Gumy L. Fawcett J.W. Yeo G.S. Holt C.E. Subcellular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs.J. Neurosci. 2010; 30: 15464-15478Crossref PubMed Scopus (0) Google Scholar). This novel layer of intracellular patterning, originally thought to be exclusive to highly specialized cells where it was first discovered (Lasko, 2012Lasko P. mRNA localization and translational control in Drosophila oogenesis.Cold Spring Harb. Perspect. Biol. 2012; 4: 4Crossref Scopus (0) Google Scholar), may occur widely in many cell types, as suggested by the localization of subsets of mRNAs to cell protrusions in migrating fibroblasts (Lawrence and Singer, 1986Lawrence J.B. Singer R.H. Intracellular localization of messenger RNAs for cytoskeletal proteins.Cell. 1986; 45: 407-415Abstract Full Text PDF PubMed Google Scholar, Mili et al., 2008Mili S. Moissoglu K. Macara I.G. Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions.Nature. 2008; 453: 115-119Crossref PubMed Scopus (0) Google Scholar) (Figure 1). RNA localization may be an evolutionarily conserved mechanism that decentralizes genomic information and delegates its control to subcellular compartments (Holt and Schuman, 2013Holt C.E. Schuman E.M. The central dogma decentralized: new perspectives on RNA function and local translation in neurons.Neuron. 2013; 80: 648-657Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). The genetic information encoded in the nucleus provides the supply of mRNAs by transcription from which specific sets of mRNAs are chosen for subcellular localization. Chosen mRNAs are targeted to multiple locations while their translation is repressed during their transit (Erickson and Lykke-Andersen, 2011Erickson S.L. Lykke-Andersen J. Cytoplasmic mRNP granules at a glance.J. Cell Sci. 2011; 124: 293-297Crossref PubMed Scopus (0) Google Scholar, Krichevsky and Kosik, 2001Krichevsky A.M. Kosik K.S. Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation.Neuron. 2001; 32: 683-696Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The composition of transported mRNAs is regulated by both cell-intrinsic (Gumy et al., 2011Gumy L.F. Yeo G.S. Tung Y.C. Zivraj K.H. Willis D. Coppola G. Lam B.Y. Twiss J.L. Holt C.E. Fawcett J.W. Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization.RNA. 2011; 17: 85-98Crossref PubMed Scopus (0) Google Scholar, Taylor et al., 2009Taylor A.M. Berchtold N.C. Perreau V.M. Tu C.H. Li Jeon N. Cotman C.W. Axonal mRNA in uninjured and regenerating cortical mammalian axons.J. Neurosci. 2009; 29: 4697-4707Crossref PubMed Scopus (163) Google Scholar, Zivraj et al., 2010Zivraj K.H. Tung Y.C. Piper M. Gumy L. Fawcett J.W. Yeo G.S. Holt C.E. Subcellular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs.J. Neurosci. 2010; 30: 15464-15478Crossref PubMed Scopus (0) Google Scholar) and -extrinsic signals (Dictenberg et al., 2008Dictenberg J.B. Swanger S.A. Antar L.N. Singer R.H. Bassell G.J. A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome.Dev. Cell. 2008; 14: 926-939Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, Mingle et al., 2005Mingle L.A. Okuhama N.N. Shi J. Singer R.H. Condeelis J. Liu G. Localization of all seven messenger RNAs for the actin-polymerization nucleator Arp2/3 complex in the protrusions of fibroblasts.J. Cell Sci. 2005; 118: 2425-2433Crossref PubMed Scopus (0) Google Scholar, Willis et al., 2007Willis D.E. van Niekerk E.A. Sasaki Y. Mesngon M. Merianda T.T. Williams G.G. Kendall M. Smith D.S. Bassell G.J. Twiss J.L. Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs.J. Cell Biol. 2007; 178: 965-980Crossref PubMed Scopus (153) Google Scholar). Thus, mRNAs are much more than simple “messengers” that deliver the genetic information from DNA to the protein synthetic apparatus, inasmuch as subcellularly targeted collections of mRNAs can function as a genomic outpost. There, functionally related mRNAs can be synchronously translated according to biological needs, providing an efficient means for coordinate control of gene expression (Keene and Tenenbaum, 2002Keene J.D. Tenenbaum S.A. Eukaryotic mRNPs may represent posttranscriptional operons.Mol. Cell. 2002; 9: 1161-1167Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar), comparable to the efficient bacterial operon system (Jacob et al., 1960Jacob F. Perrin D. Sanchez C. Monod J. [Operon: a group of genes with the expression coordinated by an operator].C. R. Hebd. Seances Acad. Sci. 1960; 250: 1727-1729PubMed Google Scholar). Moreover, it is becoming increasingly clear that dysfunctional RNA localization and translation represent one of most common molecular pathologies of neurodevelopmental and neurodegenerative diseases (Kelleher and Bear, 2008Kelleher 3rd, R.J. Bear M.F. The autistic neuron: troubled translation?.Cell. 2008; 135: 401-406Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, Jung et al., 2012Jung H. Yoon B.C. Holt C.E. Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair.Nat. Rev. Neurosci. 2012; 13: 308-324Crossref PubMed Scopus (3) Google Scholar, Liu-Yesucevitz et al., 2011Liu-Yesucevitz L. Bassell G.J. Gitler A.D. Hart A.C. Klann E. Richter J.D. Warren S.T. Wolozin B. Local RNA translation at the synapse and in disease.J. Neurosci. 2011; 31: 16086-16093Crossref PubMed Scopus (0) Google Scholar, Ramaswami et al., 2013Ramaswami M. Taylor J.P. Parker R. Altered ribostasis: RNA-protein granules in degenerative disorders.Cell. 2013; 154: 727-736Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, Wang et al., 2007Wang W. van Niekerk E. Willis D.E. Twiss J.L. RNA transport and localized protein synthesis in neurological disorders and neural repair.Dev. Neurobiol. 2007; 67: 1166-1182Crossref PubMed Scopus (0) Google Scholar). In this review, we present localized translation as a distinct mode of gene expression control that positions gene function with extreme spatiotemporal precision, efficiency, and flexibility. We assess current knowledge of how distinct subsets of mRNAs might be targeted to subcellular locations where they await a signal to proceed synthesizing proteins and relate how these RNA-based mechanisms might be linked to general biological themes of Location Matters and Decoding the Brain, which are covered elsewhere in this special reviews issue. Synthesizing a protein where and when it is needed provides several advantages over transporting a pre-existing protein from one place in the cell to another. Local synthesis confers ultimate precision in protein localization, as a protein is present only where it is needed and not anywhere else. On-site synthesis instantly satisfies the biological demand for a protein without any delay in its transport. Additionally, removing the reliance on a protein-encoded transport signal means that the same protein can be targeted to diverse subcellular compartments without risking changing its structure or compromising its function. In this latter case, the localization information can be encoded in the mRNA untranslated region (UTR) rather than in the protein-coding region. Finally, many copies of proteins can, in theory, be made from one mRNA molecule by multiple rounds of translation conferring an economical advantage. Newly made proteins can play at least two roles. First, they harbor unique information distinct from pre-existing ones, and thus can be used to deliver an additional layer of signaling information (Holt and Bullock, 2009Holt C.E. Bullock S.L. Subcellular mRNA localization in animal cells and why it matters.Science. 2009; 326: 1212-1216Crossref PubMed Scopus (0) Google Scholar). An alternative, but not mutually exclusive role of newly made proteins is to replenish damaged, degraded, or inactivated proteins to maintain local proteome homeostasis. Location. The location of the birth of a protein encodes important signaling information. The growth cone, the tip of a growing axon, is thought to be nature’s most sensitive sensor of chemical gradients as it can detect a concentration difference as little as 0.1% (Rosoff et al., 2004Rosoff W.J. Urbach J.S. Esrick M.A. McAllister R.G. Richards L.J. Goodhill G.J. A new chemotaxis assay shows the extreme sensitivity of axons to molecular gradients.Nat. Neurosci. 2004; 7: 678-682Crossref PubMed Scopus (153) Google Scholar). When challenged with a gradient of an attractive guidance cue, netrin-1 or brain-derived neurotrophic factor (BDNF), asymmetric translation of β-actin mRNA occurs within the growth cone on the side nearest the source of the gradient (Leung et al., 2006Leung K.M. van Horck F.P. Lin A.C. Allison R. Standart N. Holt C.E. Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1.Nat. Neurosci. 2006; 9: 1247-1256Crossref PubMed Scopus (224) Google Scholar). This precise spatial regulation of mRNA translation (growth cones are around 5 μm across) precedes and is required for the growth cone’s ability to turn toward the source of the guidance cue (Leung et al., 2006Leung K.M. van Horck F.P. Lin A.C. Allison R. Standart N. Holt C.E. Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1.Nat. Neurosci. 2006; 9: 1247-1256Crossref PubMed Scopus (224) Google Scholar, Yao et al., 2006Yao J. Sasaki Y. Wen Z. Bassell G.J. Zheng J.Q. An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance.Nat. Neurosci. 2006; 9: 1265-1273Crossref PubMed Scopus (0) Google Scholar). In neuronal dendrites, on an even smaller scale, synaptic activation induces transcript-specific translation only at the stimulated synapses (Wang et al., 2009Wang D.O. Kim S.M. Zhao Y. Hwang H. Miura S.K. Sossin W.S. Martin K.C. Synapse- and stimulus-specific local translation during long-term neuronal plasticity.Science. 2009; 324: 1536-1540Crossref PubMed Scopus (115) Google Scholar), allowing context-dependent, spatially restricted changes in synaptic structure and function. There is evidence that transcription factors—such as CREB (cyclic AMP-responsive element-binding protein) (Cox et al., 2008Cox L.J. Hengst U. Gurskaya N.G. Lukyanov K.A. Jaffrey S.R. Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival.Nat. Cell Biol. 2008; 10: 149-159Crossref PubMed Scopus (0) Google Scholar), STAT3 (signal transducer and activator of transcription 3) (Ben-Yaakov et al., 2012Ben-Yaakov K. Dagan S.Y. Segal-Ruder Y. Shalem O. Vuppalanchi D. Willis D.E. Yudin D. Rishal I. Rother F. Bader M. et al.Axonal transcription factors signal retrogradely in lesioned peripheral nerve.EMBO J. 2012; 31: 1350-1363Crossref PubMed Scopus (94) Google Scholar), and SMADs (homologs of C. elegans small body size and Drosophila mothers against decapentaplegic) (Ji and Jaffrey, 2012Ji S.J. Jaffrey S.R. Intra-axonal translation of SMAD1/5/8 mediates retrograde regulation of trigeminal ganglia subtype specification.Neuron. 2012; 74: 95-107Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)—synthesized in distal axons interact with the local signaling milieu immediately after their synthesis, and carry this unique birth-place information to the nucleus where it modulates their gene regulatory function. Another intriguing case, although it remains to be corroborated, is the recent report of nuclear translation. Peptides encoded in the intron are generated by an unknown mode of translation before pre-mRNA splicing and subsequent mRNA nuclear export. The peptides are presented to the major histocompatibility complex (MHC) I pathway in cells expressing all possible splice variants during T-cell-negative selection, thus preventing autoimmune reactions (Apcher et al., 2013Apcher S. Millot G. Daskalogianni C. Scherl A. Manoury B. Fåhraeus R. Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway.Proc. Natl. Acad. Sci. USA. 2013; 110: 17951-17956Crossref PubMed Scopus (0) Google Scholar). Time. The time of the birth of a protein can also encode signaling information. Many proteins are subject to posttranslational modifications as they execute their functions or even as they age. Newly synthesized proteins thus are distinct from their existent counterparts in several important aspects. For example, little or no posttranslational modification of a “new” β-actin molecule provides information distinct from that of “old” ones that have been posttranslationally modified by glutathionylation (Wang et al., 2001Wang J. Boja E.S. Tan W. Tekle E. Fales H.M. English S. Mieyal J.J. Chock P.B. Reversible glutathionylation regulates actin polymerization in A431 cells.J. Biol. Chem. 2001; 276: 47763-47766Crossref PubMed Scopus (268) Google Scholar) or arginylation (Karakozova et al., 2006Karakozova M. Kozak M. Wong C.C. Bailey A.O. Yates 3rd, J.R. Mogilner A. Zebroski H. Kashina A. Arginylation of beta-actin regulates actin cytoskeleton and cell motility.Science. 2006; 313: 192-196Crossref PubMed Scopus (0) Google Scholar). A highly localized, sudden rise in nascent β-actin molecules, which are likely to have a faster rate of polymerization than pre-existing β-actins, may link the site of local protein synthesis and actin nucleation (Condeelis and Singer, 2005Condeelis J. Singer R.H. How and why does beta-actin mRNA target?.Biol. Cell. 2005; 97: 97-110Crossref PubMed Scopus (0) Google Scholar). In addition to generating highly localized signaling information, localized mRNA translation is used to maintain local proteome homeostasis (Alvarez et al., 2000Alvarez J. Giuditta A. Koenig E. Protein synthesis in axons and terminals: significance for maintenance, plasticity and regulation of phenotype. With a critique of slow transport theory.Prog. Neurobiol. 2000; 62: 1-62Crossref PubMed Scopus (0) Google Scholar). The mRNA encoding the activated leukocyte cell adhesion molecule (ALCAM) localizes to the neuronal axon. There, its translation is regulated by the cis-element residing in its 3′-UTR (Thelen et al., 2012Thelen K. Maier B. Faber M. Albrecht C. Fischer P. Pollerberg G.E. Translation of the cell adhesion molecule ALCAM in axonal growth cones - regulation and functional importance.J. Cell Sci. 2012; 125: 1003-1014Crossref PubMed Scopus (0) Google Scholar). ALCAM mediates homophilic adhesion of axons from the same neuronal subtype and is required for the formation of axon bundles. Excess ALCAM leads to axon bundle aggregation and prevents axonal growth, whereas too little ALCAM leads to defasciculation. Intriguingly, introduction of exogenous full-length ALCAM mRNA does not result in overexpression of ALCAM protein in axons, whereas the ALCAM mRNA lacking the 3′-UTR does, indicating that a mechanism exists to maintain the right amount of ALCAM proteins on the axonal surface by local translation. This process has parallels with the resensitization of neuronal axons to extrinsic cues. Neuronal axons navigating toward a gradient of an attractive guidance cue must maintain the ability to respond to the pre-encountered cue. The initial encounter with an extrinsic cue leads to endocytosis of the activated receptors, and local translation is required to compensate for the loss of receptors from the axonal surface and to regain the ability to respond to the same cue, a process known as adaptation (Piper et al., 2005Piper M. Salih S. Weinl C. Holt C.E. Harris W.A. Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation.Nat. Neurosci. 2005; 8: 179-186Crossref PubMed Scopus (0) Google Scholar). Similarly, localized translation coupled to nonsense-mediated decay, a process that degrades mRNAs containing a premature termination codon (PTC) preceding an exon junction complex (EJC) and that is activated after the first round of translation, maintains the right amount of Robo3.2 receptor in neuronal axons to position commissural neuronal axons in the appropriate place (Colak et al., 2013Colak D. Ji S.J. Porse B.T. Jaffrey S.R. Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay.Cell. 2013; 153: 1252-1265Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Neuronal axons can synthesize locally a significant amount of diverse proteins (10% synthesis per unit volume compared to the cell body cytoplasm) (Lee and Hollenbeck, 2003Lee S.K. Hollenbeck P.J. Organization and translation of mRNA in sympathetic axons.J. Cell Sci. 2003; 116: 4467-4478Crossref PubMed Scopus (0) Google Scholar), suggesting that localized translation may provide a quality control mechanism that ensures the optimal amount of a protein is expressed in subcellular compartments. As described above, positioning the relevant mRNAs at the appropriate place within a cell enables an accelerated response to signaling inputs. With mRNAs stockpiled at distinct locations, there is little time spent moving proteins through large regions of cytoplasm. Translational activation of selected mRNAs at sites within cells draws on established control mechanisms. Translational control provides a powerful means to induce rapid changes in protein amounts and, indeed, the abundance of a protein in mammalian cells can be best predicted by the rate of mRNA translation rather than by mRNA abundance (Schwanhäusser et al., 2011Schwanhäusser B. Busse D. Li N. Dittmar G. Schuchhardt J. Wolf J. Chen W. Selbach M. Global quantification of mammalian gene expression control.Nature. 2011; 473: 337-342Crossref PubMed Scopus (1577) Google Scholar). Translation is controlled via a large number of mechanisms (reviewed in Sonenberg and Hinnebusch, 2009Sonenberg N. Hinnebusch A.G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets.Cell. 2009; 136: 731-745Abstract Full Text Full Text PDF PubMed Scopus (1107) Google Scholar), including changes in the amounts and activities of translation components: ribosomes, translation factors and tRNAs. The best understood regulatory step is the phosphorylation of translation factors and their regulators, particularly that of key eukaryotic translation initiation factors (eIFs). All eukaryotic nuclear-transcribed mRNAs possess a 5′-end cap structure. Two macromolecular complexes that function in cap-dependent translation initiation, the eIF4F and the 43S preinitiation complex, are the major targets of the translational regulation (Figure 2A). eIF4F is a heteromeric complex (Edery et al., 1983Edery I. Hümbelin M. Darveau A. Lee K.A. Milburn S. Hershey J.W. Trachsel H. Sonenberg N. Involvement of eukaryotic initiation factor 4A in the cap recognition process.J. Biol. Chem. 1983; 258: 11398-11403PubMed Google Scholar, Grifo et al., 1983Grifo J.A. Tahara S.M. Morgan M.A. Shatkin A.J. Merrick W.C. New initiation factor activity required for globin mRNA translation.J. Biol. Chem. 1983; 258: 5804-5810Abstract Full Text PDF PubMed Google Scholar) that binds the cap structure and is composed of eIF4A (RNA helicase), eIF4E (cap-binding protein) (Sonenberg et al., 1979Sonenberg N. Rupprecht K.M. Hecht S.M. Shatkin A.J. Eukaryotic mRNA cap binding protein: purification by affinity chromatography on sepharose-coupled m7GDP.Proc. Natl. Acad. Sci. USA. 1979; 76: 4345-4349Crossref PubMed Google Scholar) and eIF4G (scaffolding protein) that binds both eIF4E and eIF4A (Figure 2A). After binding to the cap, eIF4F unwinds the mRNA 5′-proximal secondary structure to facilitate the binding of the 43S preinitiation complex (see below). eIF4F Formation Is Regulated by the Phosphorylation Status of 4E-BPs. Because eIF4E generally exhibits the lowest expression level of all eIFs, the cap-recognition step by eIF4E is rate limiting for translation and a major target for regulation (Gingras et al., 1999Gingras A.C. Raught B. Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.Annu. Rev. Biochem. 1999; 68: 913-963Crossref PubMed Scopus (1449) Google Scholar). The best characterized mechanism that controls the incorporation of eIF4E into the cap-binding complex is that exerted by members of the eIF4E-binding protein (4E-BP) family: 4E-BP1, 4E-BP2, and 4E-BP3 (Pause et al., 1994Pause A. Belsham G.J. Gingras A.C. Donzé O. Lin T.A. Lawrence Jr., J.C. Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function.Nature. 1994; 371: 762-767Crossref PubMed Scopus (0) Google Scholar). 4E-BPs and eIF4G share a common eIF4E-binding motif, through which they compete for the binding to eIF4E (Figure 2A). Hypophosphorylated 4E-BPs bind eIF4E preventing it from associating with eIF4G to form the eIF4F complex (Gingras et al., 1999Gingras A.C. Raught B. Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.Annu. Rev. Biochem. 1999; 68: 913-963Crossref PubMed Scopus (1449) Google Scholar). mTORC1 Phosphorylates 4E-BPs. Phosphorylation of 4E-BPs releases eIF4E to promote the formation of the eIF4F complex and is, therefore, one of the rate-limiting steps in cap-dependent translation (Gingras et al., 1999Gingras A.C. Raught B. Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.Annu. Rev. Biochem. 1999; 68: 913-963Crossref PubMed Scopus (1449) Google Scholar). 4E-BPs’ phosphorylation is mainly controlled by the target of rapamycin (TOR), an evolutionarily conserved serine-threonine protein kinase of the phosphatidylinositol 3-kinase (PI3K)-related kinase family (Laplante and Sabatini, 2012Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (2281) Google Scholar) (Figure 2B). TOR acts as a major sensor that integrates extracellular inputs, such as insulin, growth factors, and nutrients, and intracellular levels of oxygen, energy levels, and amino acids to effect outputs including cell growth, proliferation and autophagy (Hay and Sonenberg, 2004Hay N. Sonenberg N. Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945Crossref PubMed Scopus (2338) Google Scholar). Tor genes were first discovered in yeast following a forward genetic screen for mutations that confer resistance to the antifungal agent rapamycin (Heitman et al., 1991Heitman J. Movva N.R. Hall M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast.Science. 1991; 253: 905-909Crossref PubMed Google Scholar), and subsequently its homologs were identified in mammals (mammalian/mechanistic target of rapamycin; mTOR) (Brown et" @default.
• W2018404810 created "2016-06-24" @default.
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• W2018404810 date "2014-03-01" @default.
• W2018404810 modified "2023-10-16" @default.
• W2018404810 title "Remote Control of Gene Function by Local Translation" @default.
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