Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response

Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 11/2009; 187(4):525-36. DOI: 10.1083/jcb.200907074
Source: PubMed

ABSTRACT Cells constantly adjust the sizes and shapes of their organelles according to need. In this study, we examine endoplasmic reticulum (ER) membrane expansion during the unfolded protein response (UPR) in the yeast Saccharomyces cerevisiae. We find that membrane expansion occurs through the generation of ER sheets, requires UPR signaling, and is driven by lipid biosynthesis. Uncoupling ER size control and the UPR reveals that membrane expansion alleviates ER stress independently of an increase in ER chaperone levels. Converting the sheets of the expanded ER into tubules by reticulon overexpression does not affect the ability of cells to cope with ER stress, showing that ER size rather than shape is the key factor. Thus, increasing ER size through membrane synthesis is an integral yet distinct part of the cellular program to overcome ER stress.

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Available from: Kurt S Thorn, Aug 17, 2015
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    • "One mode of size control invokes component-mediated regulation, whereby levels of structural components, such as proteins and lipids, determine the organelle volume/size (Chan and Marshall, 2010; Goehring and Hyman, 2012). For single-copy organelles, component upregulation can thus lead to expansion, as in the case of the ER (Kirk et al., 2010; Schuck et al., 2009), whereas in the case of multicopy organelles, it can modulate the combined compartment volume by adjusting the number, as lysosomes do (Sardiello et al., 2009). "
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    • "). From the proliferation of the ER network at the onset of the UPR one can predict that abundance and/or size of lipid droplets would be reduced because storage lipids are consumed for the production of membrane lipids (Bernales et al., 2006; Schuck et al., 2009). Persisting UPR activity, however, also reduces the cellular growth rate and thus dampens the demand for lipid metabolites. "
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    ABSTRACT: Abstract Biological membranes are a defining feature of cellular life. They serve as selective diffusion barriers, compartmentalize biochemical processes and protect the cellular milieu. We are only beginning to understand the principles underlying their homeostasis and the functional relevance of their complex compositions. Here, we summarize some recent evidences suggesting an intense crosstalk between the pathways of protein quality control and lipid homeostasis. We discuss paradigms of lipid regulation by protein degradation machineries and highlight the intricate connections between lipid droplet morphology, membrane biogenesis and ER-stress.
    Biological Chemistry 10/2013; 395(3). DOI:10.1515/hsz-2013-0235 · 2.69 Impact Factor
    • "A misbalance between SFAs and UFAs in the diet and, consequently, cells induces ER stress and can lead to cell death (Kim et al., 2008). Conversely, a massive induction of ER stress is counterbalanced by the increased utilization of FAs for lipid synthesis and expansion of the ER (Bernales et al., 2006; Schuck et al., 2009). This introduces a conundrum surrounding the nature by which ER stress is modulated by lipid species. "
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    ABSTRACT: Biological membranes are complex, and the mechanisms underlying their homeostasis are incompletely understood. Here, we present a quantitative genetic interaction map (E-MAP) focused on various aspects of lipid biology, including lipid metabolism, sorting, and trafficking. This E-MAP contains ∼250,000 negative and positive genetic interaction scores and identifies a molecular crosstalk of protein quality control pathways with lipid bilayer homeostasis. Ubx2p, a component of the endoplasmic-reticulum-associated degradation pathway, surfaces as a key upstream regulator of the essential fatty acid (FA) desaturase Ole1p. Loss of Ubx2p affects the transcriptional control of OLE1, resulting in impaired FA desaturation and a severe shift toward more saturated membrane lipids. Both the induction of the unfolded protein response and aberrant nuclear membrane morphologies observed in cells lacking UBX2 are suppressed by the supplementation of unsaturated FAs. Our results point toward the existence of dedicated bilayer stress responses for membrane homeostasis.
    Molecular cell 07/2013; 51(4). DOI:10.1016/j.molcel.2013.06.014 · 14.46 Impact Factor
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