Abstract
The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes.
Highlights
The ER is best known as the gateway to the secretory pathway
This regulation constitutes a self-contained system in which ER stress leads to transcriptional induction of genes encoding ER chaperones and other proteins that grease the wheels of secretory pathway function, thereby alleviating ER stress and shutting the response off (Travers et al, 2000)
Rather than providing an exhaustive account of all possible means by which mRNA abundance might be controlled by the unfolded protein response (UPR), here we describe the general principles by which such regulation can occur and provide illustrative examples that emphasize the diverse physiological consequences of such pathways
Summary
The ER is best known as the gateway to the secretory pathway. As the site of synthesis for nascent secretory proteins and resident lumenal and transmembrane proteins of the endomembrane system, the ER shepherds the folding, oxidation, modification, and assembly of approximately one-third of the cellular proteome—or more in cell types specialized for protein secretion such as antibody-secreting plasma B lymphocytes or endocrine or exocrine cells (Huh et al, 2003; Tagliavacca et al, 2003). JNK activation leads to phosphorylation of the bZIP transcription factor C-JUN (Urano et al, 2000), which has been implicated in ER stress-mediated regulation in cultured neurons of the gene encoding methylenetetrahydrofolate reductase, which participates in folate and homocysteine metabolism (Leclerc and Rozen, 2008), and of Gpt and Got in the liver, which encode the liver enzymes AST and ALT that are released from the liver upon damage (Josekutty et al, 2013) These examples notwithstanding, the contributions of IRE1α/TRAF2-dependent signaling to the sum of ER stress-mediated transcriptome control are poorly understood. As with IRE1α-dependent signaling modules, the global contribution of these pathways to mRNA regulation during ER stress is not clear
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