Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response

By S. Bernales, K. McDonald, Peter Walter. PLoS Biology, 2006

1,036 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/e5e1da19a45981456d0dc84073ce108356974529

How researchers see this paper

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In Cell Biology

1. Peter Walter
2. John Calvin Reed
3. H. Chae
4. Hyung-Ryong Kim
5. M. Cnop
6. Michael D. Blower
7. D. Schwarz
8. D. Ron

In Epidemiology

1. John Calvin Reed
2. Peter Walter
3. D. Ron
4. M. Cnop
5. Ivan Dikic
6. S. Martens
7. R. Sano
8. H. Chae

Citations in the corpus

• Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities (2008, background): “Moreover, it is becoming increasingly apparent that ER stress induces autophagy”
• Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. (2007, background): “Both immunostaining with an anti-calnexin antibody and electron microscopic analysis indicated that the vacuoles consisted of dilated and expanded ER lumens (Figure 6, D and E), which most likely indicated ER stress.(3,21) Furthermore, there was a significant increase of proteins involved in the UPR”
• ER stress-induced cell death mechanisms. (2013, background): “ER stress leads to activation of two protein degradation pathways, the ubiquitin-proteasome via ERAD and lysosome-mediated protein degradation via autophagy (reviewed in [48]).”
• ER stress: Autophagy induction, inhibition and selection (2015, background): “Specifically, electron microscopy studies in yeast revealed that ER volume increases 5-fold under ER stress and that cells undergoing such stress exhibit concomitant increases in autophagosome abundance.(94) According to Ogata et al.”
• Autophagy Suppresses Tumorigenesis Through Elimination of p62 (2009, neutral): “and directed to autophagosomes for degradation is not known, butmay involve organelle-specific processes such asmitophagy and ER-phagy (Bernales et al., 2006; Kim et al., 2007).”
• Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium (2007, neutral): “The data showing that ER itself is the major autophagosomal cargo during ER stress suggest that the pro-survival effect of autophagy in this model system could be due to augmented removal of unfolded proteins.(20) Additionally, the autophagy response may serve as a negative feedback mechanism removi”