The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis

Protein folding—the process by which a sequence of amino acids adopts the precise shape that is needed to perform a specific biological function—is one of the most important processes in all of biology. Any sequence of amino acids has the potential to fold into a large number of different shapes, and misfolded proteins can lead to toxicity and other problems. For example, all cells rely on signaling proteins in the membranes that enclose them to monitor their environment so that they can adapt to changing conditions and, in multicellular organisms, communicate with neighboring cells: without properly folded signaling proteins, chaos would ensue. Moreover, many diseases—including diabetes, cancer, viral infection and neurodegenerative disease—have been linked to protein folding processes. It is not surprising, therefore, that cells have evolved elaborate mechanisms to exert exquisite quality control over protein folding. One of these mechanisms, called the unfolded protein response (UPR), operates in a compartment within the cell known as the endoplasmic reticulum (ER). The ER is a labyrinthine network of tubes and sacs within all eukaryotic cells, and most proteins destined for the cell surface or outside the cell adopt their properly folded shapes within this compartment. If the ER does not have enough capacity to fold all of the proteins that are delivered there, the UPR switches on to increase the protein folding capacity, to expand the surface area and volume of the compartment, and to degrade misfolded proteins. If the UPR cannot adequately adjust the folding capacity of the ER to meet the demands of the cell, the UPR triggers a program that kills the cell to prevent putting the whole organism at risk. Researchers have identified the cellular components that monitor the protein folding conditions inside the ER. All eukaryotic cells, from unicellular yeasts to mammalian cells, contain a highly conserved protein-folding sensor called Ire1. In all species analyzed to date, Ire1 is known to activate the UPR through an messenger RNA (mRNA) splicing mechanism. This splicing event provides the switch that drives a gene expression program in which the production of ER components is increased to boost the protein folding capacity of the compartment. Kimmig, Diaz et al. now report the first instance of an organism in which the UPR does not involve mRNA splicing or the initiation of a gene expression program. Rather, the yeast Schizosaccharomyces pombe utilizes Ire1 to an entirely different end. The authors find that the activation of Ire1 in S. pombe leads to the selective decay of a specific class of mRNAs that all encode proteins entering the ER. Thus, rather than increasing the protein folding capacity of the ER when faced with an increased protein folding load, S. pombe cells correct the imbalance by decreasing the load. The authors also show that a lone mRNA—the mRNA that encodes the molecular chaperone BiP, which is one of the major protein-folding components in the ER—uniquely escapes this decay. Rather than being degraded, Ire1 truncates BiP mRNA and renders it more stable. By studying the UPR in a divergent organism, the authors shed new light on the evolution of a universally important process and illustrate how conserved machinery has been repurposed.