RNA exosome-driven RNA processing instructs the duration of the unfolded protein response

Upon stresses, cellular compartments initiate adaptive programs meant to restore homeostasis. Dedicated to the resolution of transient perturbations, these pathways are typically maintained at a basal level, activated upon stress, and critically downregulated upon reestablishment of cellular homeostasis. As such, prolonged activation of the unfolded protein response (UPR), a conserved adaptive transcriptional response to defective endoplasmic reticulum (ER) proteostasis, leads to cell death. Here, we elucidate an unanticipated role for the nuclear RNA exosome, an evolutionarily conserved ribonuclease complex that processes multiple classes of RNAs, in the control of UPR duration. Remarkably, the inactivation of Rrp6, an exclusively nuclear catalytic subunit of the RNA exosome, curtails UPR signaling, which is sufficient to promote the cell's resistance to ER stress. Mechanistically, accumulation of unprocessed RNA species diverts the processing machinery that maturates the messenger RNA encoding the master UPR regulator Hac1, thus restricting the UPR. Significantly, Rrp6 expression is naturally dampened upon ER stress, thereby participating in homeostatic UPR deactivation.