Figure 4. The ER as a global mRNA translation and regulation hub.

In this schematic, the diverse roles of the endoplasmic reticulum (ER) in global mRNA translation and regulation are depicted. The ER is the entry point of mRNAs encoding secretory and membrane proteins into the secretory pathway. Two modes of localization are shown. a | In one pathway, mRNAs encoding secretory and membrane proteins undergo initiation on free, cytosolic ribosomes and are targeted to the ER via the signal recognition particle (SRP) pathway. b | In the other pathway, many mRNAs, including those encoding secretory and cytosolic proteins undergo direct initiation on stably ER-bound ribosomes. c | Also shown are diverse ribosome receptors that are autonomous to translocation channels. These ribosomes can engage in the synthesis of cytosolic protein-encoding mRNAs, as well as mRNAs encoding topogenic signals. We propose that the receptor-bound, translationally active ribosome encounters an open translocation site by lateral diffusion in the ER membrane, with engagement of the nascent protein at the translocation site bringing the bound ribosome to close physical proximity to the protein-conducting channel. d | MicroRNA (miRNA)-mediated silencing is highly dependent on the ER. For endogenous miRNAs, RNA-induced silencing complex (RISC) loading, mRNA binding and Argonaute 2-mediated processing are associated with the ER membrane, whereas the cytosolic miRNAs remain inactive^51,56. Thus, compartmentalization subjects mRNAs to distinct regulatory environments depending on their localization, in which ER-localized mRNAs are targeted for silencing but the same mRNA in the cytosol may escape.