The mechanism and function of ribosome-independent association of mRNA to the endoplasmic reticulum

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The human genome contains about 23 thousand genes, each encoding a particular protein. The expression of these genes varies between cell type and can be modulated by a multitude of inputs including environmental cues. A substantial fraction of genes (~22% of the human genome) encode proteins that are either integrated into membranes or are transported across membranes to be secreted from the cell. Gene expression begins in the nucleus where a segment of DNA that contains the gene is first copied into messenger RNA (mRNA) transcripts. These mRNAs are then exported from the nucleus into the cytoplasm where protein synthesis takes place. Although most mRNAs are translated into proteins by "free" ribosomes, transcripts that encode secreted or membrane-bound proteins are translated by ribosomes bound to the surface of the endoplasmic reticulum (ER), a large reticular organelle found in almost all cells. Classic studies from the 1970s demonstrated that these mRNAs are targeted and maintained on the ER by associating to the ribosome during translation. It however was unclear whether additional alternative mechanisms existed to target and maintain these mRNAs on the ER independently of ribosomes or translation. Using novel approaches we have demonstrated that many mRNAs that encode secreted or membrane-bound proteins can target and be maintained on the ER even either when translation is inhibited or when ribosomes are disassembled. In addition, we have identified potential mRNA receptors that may be responsible for this translation-independent targeting. In this proposal I will describe our plans to identify which transcripts use this alternative targeting/maintenance mechanism, identify elements present within the RNA that are responsible for targeting, and identify the putative mRNA receptors on the ER that bind to these elements. Through this work, I hope to gain a deeper understanding of how the cytoplasmic localization of mRNA contributes to cellular organization and various basic cellular functions such as secretion.