Author response: Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe
Year: 2017
Type: peer-review
Abstract: Most proteins need to fold into a specific shape in order to work properly. As such, cells have developed a number of ways to sense and respond to stressful conditions that cause their proteins to fold incorrectly. One place this happens is within a network of tubes inside the cell called the endoplasmic reticulum; this is where proteins that are destined for the cell surface or other compartments in the cell become folded. The endoplasmic reticulum has a limited capacity to fold proteins. When it is overwhelmed, the cell temporarily stops making the proteins that use up this capacity. This action makes up part of a larger set of responses collectively referred to as the “unfolded protein response”. During the unfolded protein response, the production of some proteins is turned off when an enzyme called Ire1 cuts the transcript molecules that contain the instructions to build these proteins. Cutting these transcripts, however, creates a problem: it interrupts the translation of the transcript by the ribosome, the molecular machine that reads the genetic code to build proteins. Usually, a ribosome only comes off of a transcript when it arrives at a specific stop signal. Yet, ribosomes that run to the ends of broken transcripts never reach this signal and instead have to be rescued. If left without rescue, these stalled ribosomes could never be used again for translation of other transcripts, and the cell would lose the ability to make more proteins. Guydosh, Kimmig et al. searched for new genes in the yeast Schizosaccharomyces pombe that are involved in the part of the unfolded protein response that occurs after the actions of the Ire1 enzyme. This search revealed that cells missing so-called ribosome rescue proteins (namely Dom34 and Hbs1) grow slowly under conditions that cause proteins to fold incorrectly. Guydosh, Kimmig et al. then looked to see where on the transcripts the ribosomes stall and remain un-rescued in the absence of these ribosome rescue proteins. These sites corresponded to places that were cut by Ire1, the majority of which were previously unknown. Together these findings indicate that ribosome rescue is a key part of the unfolded protein response in S. pombe because it removes ribosomes that stall at the broken ends of transcript molecules cut by the Ire1 enzyme. An efficient and well-controlled response to conditions that cause proteins to fold incorrectly is important for human health. Loss of this control can lead to disorders as diverse as atherosclerosis, cancer and neurological diseases. By revealing that the unfolded protein response uses the ribosome rescue pathway, the findings improve our understanding of these health conditions and may open the door to new research and treatments.
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W2989450152