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Localization of mRNAs to the endoplasmic reticulum

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Almost all cells use mRNA localization to establish spatial control of protein synthesis. One of the best‐studied examples is the targeting and anchoring of mRNAs encoding secreted, organellar, and membrane‐bound proteins to the surface of the endoplasmic reticulum (ER). In this review, we provide a historical perspective on the research that elucidated the canonical protein‐mediated targeting of nascent‐chain ribosome mRNA complexes to the surface of the ER. We then discuss subsequent studies which provided concrete evidence that a subpopulation of mRNAs utilize a translation‐independent mechanism to localize to the surface of this organelle. This alternative mechanism operates alongside the signal recognition particle (SRP) mediated co‐translational targeting pathway to promote proper mRNA localization to the ER. Recent work has uncovered trans‐acting factors, such as the mRNA receptor p180, and cis‐acting elements, such as transmembrane domain coding regions, that are responsible for this alternative mRNA localization process. Furthermore, some unanticipated observations have raised the possibility that this alternative pathway may be conserved from bacteria to mammalian cells. WIREs RNA 2014, 5:481–492. doi: 10.1002/wrna.1225 This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation RNA Export and Localization > RNA Localization

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Targeting secretory proteins to the endoplasmic reticulum. (a) SRP‐mediated protein localization to the ER. In this pathway, mRNAs encoding secretory proteins are translated by cytoplasmic ribosomes. After the N‐terminal hydrophobic signal sequence exits the ribosome, the cytosolic signal recognition particle (SRP) binds to it, halts the translation, and then delivers the ribosome‐nascent peptide–mRNA complex to the ER by interacting with the SRP receptor (SR). At the ER, the signal sequence is then inserted into the sec61 translocon, and translation resumes. (b–d) SRP‐independent localization to the ER. (b) In yeast, post‐translational translocation of proteins requires the Sec62/Sec63 and translocon complexes. The mammalian versions of Sec62 and Sec63 have gained additional positively charged cytoplasmic domains which allow them to interact with the ribosome. Sec62/Sec63‐dependent translocation functions independently of SRP. (c) Membrane proteins that do not encode an N‐terminal signal sequence but instead contain a C‐terminal transmembrane domain (also called tail‐anchored proteins) are thought to be targeted to the ER post‐translationally via the GET pathway. In the mammalian system, a pre‐targeting complex recognizes the TMD as it exits the ribosome. The TMD is then transferred to a TRC40 oligomer that acts as a chaperone. Two TRC40 receptors, CAML and WRB, have been identified on the surface of the ER; however, it is unclear how these latter factors mediate translocation. It is also unclear whether the translocon is involved in the direct insertion of tail‐anchored substrates. (d) Calmodulin (CaM) might also play a role in mediating the insertion of small secretory proteins or TA proteins into the ER membrane.
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Translation‐independent mRNA localization to the ER via p180. Recent studies have shown that mRNAs can be targeted to the ER by p180 in the absence of translation. While details of this targeting pathway are still being elucidated, it is clear that this activity differs between various mRNA species. As p180 is unlikely to provide any specificity, features that distinguish targeting mRNAs from non‐targeting mRNAs are likely due to an unidentified cytosolic RNA binding protein ‘X’. These mRNAs are then maintained on the ER by p180 nonspecifically and can gain access to ER‐bound ribosomes. Several studies suggest that p180 interacts directly with ribosomes and indirectly with translocons, and thus may facilitate the general synthesis of membrane‐bound and secretory proteins.
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Schematic of p180 and kinectin. Both kinectin and p180 contain a short N‐terminal luminal domain, followed by a single transmembrane domain and a large cytosolic C‐terminal region. For p180 the cytosolic domain is comprised of a highly positively charged lysine‐rich region, a 10‐amino acid (decapeptide) sequence that is repeated 54 times in tandem, and a coiled‐coil domain. Kinectin shares a low degree of similarity to p180 throughout its length; however, it lacks the decapeptide repeats.
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Translation > Translation Regulation
Translation > Translation Mechanisms
RNA Export and Localization > RNA Localization

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