Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response

Abstract

The protein folding capacity of the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR senses unfolded proteins in the ER lumen and transmits that information to the cell nucleus, where it drives a transcriptional program that is tailored to re-establish homeostasis. Using thin section electron microscopy, we 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. In analogy to pexophagy and mitophagy, which are autophagic processes that selectively sequester and degrade peroxisomes and mitochondria, the ER-specific autophagic process described utilizes several autophagy genes: they 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.

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

“…55 Moreover, mild to moderate stress supports cell survival (protective autophagy) and if it further accumulates, it will merge to a point of no return by triggering apoptosis. 55 Interestingly, several reports have unveiled that blocking of autophagy can stimulate ER stress-induced cell death, 56,57 but the forceful abrogation of a physiologically relevant biological process poses an undesirable threat to normal cells. From that standpoint, activation of apoptotic pathways by inducing the expression of the tumor suppressor PAWR would be more purposeful as a therapeutic strategy.…”

Autophagy at the crossroads of catabolism and anabolism

“…Autophagy selectively degrades aggregated proteins that accumulate in the ER lumen, such as the mutant secretory protein α1-antitrypsin 121 . Additionally, studies of yeast and mammalian cells demonstrate that autophagy mediates ER homeostasis by selectively segregating portions of this organelle network; this process has been termed ER-phagy or reticulophagy [122][123][124][125] . In addition to protein aggregates, selective autophagy is an important mechanism for the degradation of organelles.…”

Autophagy in the liver

“…A similar phenomenon was observed recently in yeast, which was under ER stress. 92 It is possible that the unfolded protein response pathway and/or ER calcium leakage may also be involved in the induction of autophagy, as in the case of ER-retained misfolded proteins (see above).…”