The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum.

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2014-09

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Abstract

The unfolded protein response (UPR) is a stress response program that reprograms cellular translation and gene expression in response to proteotoxic stress in the endoplasmic reticulum (ER). One of the primary means by which the UPR alleviates this stress is by reducing protein flux into the ER via a general suppression of protein synthesis and ER-specific mRNA degradation. We report here an additional UPR-induced mechanism for the reduction of protein flux into the ER, where mRNAs that encode signal sequences are released from the ER to the cytosol. By removing mRNAs from the site of translocation, this mechanism may serve as a potent means to transiently reduce ER protein folding load and restore proteostasis. These findings identify the dynamic subcellular localization of mRNAs and translation as a selective and rapid regulatory feature of the cellular response to protein folding stress.

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10.1016/j.cell.2014.08.012

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Reid, David W, Qiang Chen, Angeline S-L Tay, Shirish Shenolikar and Christopher V Nicchitta (2014). The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum. Cell, 158(6). pp. 1362–1374. 10.1016/j.cell.2014.08.012 Retrieved from https://hdl.handle.net/10161/17236.

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Scholars@Duke

Nicchitta

Christopher Vincent Nicchitta

Professor of Cell Biology

  Our laboratory studies the cellular architecture and regulation of protein synthesis, with the goal of understanding how cells regulate the subcellular organization and temporal dynamics of protein synthesis. We focus on mRNA localization - the process by which cells control where and when a protein is synthesized by localizing its mRNA to a discrete location(s) in the cell. Such regulation is critical for many aspects of cell dynamics, cell signaling and cell division. Of the diverse mRNA localization phenomena that have been identified to date, the most prominent is mRNA localization to the endoplasmic reticulum (ER). mRNA localization to the ER operates on an unusually large scale (essentially the entire mRNA transcriptome is partially represented on the ER, with those mRNAs encoding secretory and membrane proteins being highly ER-enriched), and continuously– all newly exported mRNAs undergo selection for translation in the cytosol and/or the ER compartments.

We use a broad array of experimental approaches - biochemistry, cell biology, genomics, and computational biology - and are focusing on several related themes. First, we are working to identify the mRNA-encoded signals used to target mRNAs to the ER as well as the cellular factors that recognize these signals. One mechanism, in which a signal in nascent secretory and membrane proteins directs mRNA recruitment to the ER, has been previously described. It is clear though that there are multiple pathways that direct mRNAs to the ER, including pathways that direct cytosolic and nucleoplasmic protein-encoding mRNAs to the ER. We are also investigating how, once localized, mRNAs are anchored to the ER membrane. In a recent study, we reported that the cohort of mRNAs encoding organelle resident proteins(e.g., nuclear envelope, ER, Golgi, lysosomes, peroxisomes) are localized tothe ER and directly anchored to components of the ER membrane. We are very interested in understanding the cis-encoded anchoring signals and the integral membrane proteins that function in mRNA anchoring to biological membrane, and lastly, how direct mRNA anchoring influences mRNA translation and mRNA stability.

In parallel efforts, we discovered that mRNA translation is under distinct regulatory control in the cytosol and ER compartments, with translation being 3-5 fold more efficient on the ER. These differences are substantial and suggest that mRNA localization to the ER may represent an important post-transcriptional gene expression mechanism. To gain insight into the mechanisms and factors responsible for the compartmental regulation of mRNA translation we are using traditional biochemical approaches (pulse-labeling, cell fractionation, immunoprecipitation, proteomics) as well as genomic approaches (ribosome footprinting, deep sequencing).


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