| The unfolded protein response (UPR) is an intracellular signaling pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). UPR activation triggers an extensive transcriptional response, which adjusts the ER protein folding capacity according to need. As such, the UPR constitutes a paradigm of an intracellular control mechanism that adjusts organelle abundance in response to environmental or developmental clues. The pathway involves activation of ER unfolded protein sensors that operate in parallel circuitries to transmit information across the ER membrane, activating a set of downstream transcription factors by mechanisms that are unusual yet rudimentarily conserved in all eukaryotes.; Our research has identified a heretofore unrecognized pathway in yeast Saccharomyces cerevisiae that regulates the transcription of the gene that encodes the main UPR transcription factor, HAC1. The resulting increase in Hac1p production, combined with the production or activation of a putative UPR modulatory factor, is necessary to qualitatively modify the cellular response in order to survive the inducing conditions. This parallel ER-to-nucleus signaling pathway thereby serves to modify the UPR-driven transcriptional program. The results suggest a surprising conservation among all eukaryotes of the ways by which the elements of the UPR signaling circuit are connected. Our studies have shown that by adding an additional signaling element to the basic UPR circuit, a simple switch is transformed into a complex response.; We also found that yeast cells expand their ER volume at least 5-fold under UPR-inducing conditions. Surprisingly, we discovered that ER proliferation is accompanied by the formation of autophagosome-like structures that are densely and selectively packed with membrane stacks derived from the UPR-expanded ER. This ER-specific autophagic described utilizes several autophagy genes that are induced by the UPR and are essential for the survival of cells subjected to severe ER stress. Intriguingly, cell survival does not require vacuolar proteases, indicating that ER sequestration into autophagosome-like structures, rather than their degradation, is the important step. Selective ER sequestration may help cells to maintain a new steady-state level of ER abundance even in the face of continuously accumulating unfolded proteins. |
