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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2019)

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, protein trafficking, and lipid synthesis. As such, cells have evolved a quality control system known as the ER Unfolded Protein Response (UPRER). Capable of monitoring protein folding and membrane lipid composition to preserve ER homeostasis, the UPRER is crucial for responding to cellular stress brought on by increased metabolic demand, environmental factors, and aging. In this study, we have identified let-767 as an essential gene for ER homeostasis. Through an RNAi screen of lipid droplet associated genes, we found that knockdown of let-767 resulted in reduced lipid droplets, aberrant ER morphology, and compromised UPRER induction, which impacted growth and lifespan. We found that these deficiencies in ER quality were independent of let-767’s previously characterized function in mono-methyl branched chain fatty acid synthesis (mmBCFAs), as supplementation of mmBCFAs did not ameliorate the detrimental phenotypes. However, supplementation of whole animal lysate was able to rescue the lipid droplet depletion, ER morphology, and animal growth, but not the UPRER function. The UPRER induction was instead rescued by reducing the let-767 pathway through knockdown of the upstream transcription factor sbp-1, suggesting accumulation of a potential toxic metabolite within the let-767 pathway. Our results indicate that let-767 may play a more significant role in lipid metabolism than has been previously described and highlight the importance of lipid homeostasis to protein quality control.

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Cover page: Lipid homeostasis is essential for endoplasmic reticulum protein quality control
  • Article
  • Peer Reviewed
UC Berkeley Previously Published Works (2016)
Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65. While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs. Thus, a metabolic stress response is established and propagated into adulthood of animals through specific epigenetic modifications that allow for selective gene expression and lifespan extension.
    Cover page: Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPRmt
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2020)
    In multicellular organisms, neurons integrate a diverse array of external cues to affect downstream changes in organismal health. Specifically, activation of the endoplasmic reticulum (ER) unfolded protein response (UPRER) in neurons increases lifespan by preventing age-onset loss of ER proteostasis and driving lipid depletion in a cell non-autonomous manner. The mechanism of this communication is dependent on the release of small clear vesicles from neurons. We find dopaminergic neurons are necessary and sufficient for activation of cell non-autonomous UPRER to drive lipid depletion in peripheral tissues, whereas serotonergic neurons are sufficient to drive protein homeostasis in peripheral tissues. These signaling modalities are unique and independent and together coordinate the beneficial effects of neuronal cell non-autonomous ER stress signaling upon health and longevity.
      Cover page: Divergent Nodes of Non-autonomous UPRER Signaling through Serotonergic and Dopaminergic Neurons
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      The dysfunction of mitochondria is associated with the physiological consequences of aging and many age-related diseases. Therefore, critical quality control mechanisms exist to protect mitochondrial functions, including the unfolded protein response of the mitochondria (UPRMT). However, it is still unclear how UPRMT is regulated in mammals with mechanistic discrepancies between previous studies. Here, we reasoned that a study of conserved mechanisms could provide a uniquely powerful way to reveal previously uncharacterized components of the mammalian UPRMT. We performed cross-species comparison of genetic requirements for survival under—and in response to—mitochondrial stress between karyotypically normal human stem cells and the nematode Caenorhabditis elegans. We identified a role for EPS-8/EPS8 (epidermal growth factor receptor pathway substrate 8), a signaling protein adaptor, in general mitochondrial homeostasis and UPRMT regulation through integrin-mediated remodeling of the actin cytoskeleton. This study also highlights the use of cross-species comparisons in genetic screens to interrogate cellular pathways.
        Cover page: Cross-species screening platforms identify EPS-8 as a critical link for mitochondrial stress and actin stabilization
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