Devin Dersh

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States

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Publications (6)44.83 Total impact

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    ABSTRACT: The tight coupling of protein folding pathways with disposal mechanisms promotes the efficacy of protein production in the endoplasmic reticulum (ER). It has been hypothesized that the ER-resident molecular chaperone GRP94 is part of this quality control coupling because it supports folding of select client proteins yet also robustly associates with the lectin OS-9, a component involved in ER-associated degradation (ERAD). To explore this possibility, we investigated potential functions for the GRP94/OS-9 complex in ER quality control. Unexpectedly, GRP94 does not collaborate with OS-9 for ERAD of misfolded substrates, nor is the chaperone required directly for OS-9 folding. Instead, OS-9 binds preferentially to a subpopulation of GRP94, which is hyper-glycosylated on cryptic N-linked glycan acceptor sites. Hyper-glycosylated GRP94 forms have non-native conformations and are less active. As a result, these species are degraded much faster than the major, mono-glycosylated form of GRP94 in an OS-9-mediated, ERAD-independent, lysosomal-like mechanism. This report therefore clarifies the role of the GRP94/OS-9 complex and describes a novel pathway by which glycosylation of cryptic acceptor sites influences the function and fate of an ER-resident chaperone.
    Preview · Article · Jun 2014 · Molecular Biology of the Cell
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    ABSTRACT: The response to endoplasmic reticulum (ER) stress relies on activation of unfolded protein response (UPR) sensors, and the outcome of the UPR depends on the duration and strength of signal. Here, we demonstrate a mechanism that attenuates the activity of the UPR sensor inositol-requiring enzyme 1α (IRE1α). A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine 148 in the lumenal domain of the sensor, which is oxidized when IRE1 is activated. PDIA6-deficient cells hyperrespond to ER stress with sustained autophosphorylation of IRE1α and splicing of XBP1 mRNA, resulting in exaggerated upregulation of UPR target genes and increased apoptosis. In vivo, PDIA6-deficient C. elegans exhibits constitutive UPR and fails to complete larval development, a program that normally requires the UPR. Thus, PDIA6 activity provides a mechanism that limits UPR signaling and maintains it within a physiologically appropriate range.
    No preview · Article · Feb 2014 · Molecular cell
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    ABSTRACT: ER stress leads to upregulation of multiple folding and quality control components, known as the unfolded protein response (UPR). Glucose Regulated Proteins 78 and 94 (GRP78/BiP and GRP94) are often upregulated coordinately as part of this homeostatic response. Given that ER chaperones have distinct sets of clients, we asked how cells respond to ablation of individual chaperones. The cellular responses to silencing BiP, GRP94, HSP47, PDIA6 and OS-9, were distinct. When BiP was silenced, a widespread UPR was observed, but when GRP94 was either inhibited or depleted by RNAi, the expression of only some genes, notably BiP and protein disulfide isomerase A6 (PDIA6) was induced. Silencing of HSP47 or OS-9 did not lead to any compensatory induction of other genes. The selective response to GRP94 depletion was distinct from a typical ER stress response, both because other UPR target genes were not affected and because the canonical UPR signaling branches were not activated. The response to silencing of GRP94 did not preclude further UPR induction when chemical stress was imposed. Importantly, re-expression of wild-type GRP94 in the silenced cells prevented the up-regulation of BiP and PDIA6, while re-expression of an ATPase-deficient GRP94 mutant did not, indicating that cells monitor the state of activity of GRP94. These findings suggest that cells are able to distinguish among folding resources and generate distinct responses.
    Full-text · Article · Aug 2012 · Journal of Cell Science
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    ABSTRACT: Many age-related diseases are known to elicit protein misfolding and aggregation. Whereas environmental stressors, such as temperature, oxidative stress, and osmotic stress, can also damage proteins, it is not known whether aging and the environment impact protein folding in the same or different ways. Using polyQ reporters of protein folding in both Caenorhabditis elegans and mammalian cell culture, we show that osmotic stress, but not other proteotoxic stressors, induces rapid (minutes) cytoplasmic polyQ aggregation. Osmotic stress-induced polyQ aggregates could be distinguished from aging-induced polyQ aggregates based on morphological, biophysical, cell biological, and biochemical criteria, suggesting that they are a unique misfolded-protein species. The insulin-like growth factor signaling mutant daf-2, which inhibits age-induced polyQ aggregation and protects C. elegans from stress, did not prevent the formation of stress-induced polyQ aggregates. However, osmotic stress resistance mutants, which genetically activate the osmotic stress response, strongly inhibited the formation of osmotic polyQ aggregates. Our findings show that in vivo, the same protein can adopt distinct aggregation states depending on the initiating stressor and that stress and aging impact the proteome in related but distinct ways.
    Full-text · Article · May 2012 · Proceedings of the National Academy of Sciences
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    Morgan E DeSantis · Devin Dersh

    Preview · Article · Jul 2010 · Disease Models and Mechanisms
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    Davide Eletto · Devin Dersh · Yair Argon
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    ABSTRACT: A system of endoplasmic reticulum (ER) chaperones has evolved to optimize the output of properly folded secretory and membrane proteins. An important player in this network is Glucose Regulated Protein 94 (GRP94). Over the last decade, new structural and functional data have begun to delineate the unique characteristics of GRP94 and have solidified its importance in ER quality control pathways. This review describes our current understanding of GRP94 and the four ways in which it contributes to the ER quality control: (1) chaperoning the folding of proteins; (2) interacting with other components of the ER protein folding machinery; (3) storing calcium; and (4) assisting in the targeting of malfolded proteins to ER-associated degradation (ERAD).
    Preview · Article · Mar 2010 · Seminars in Cell and Developmental Biology

Publication Stats

138 Citations
44.83 Total Impact Points


  • 2010-2014
    • The Children's Hospital of Philadelphia
      • Department of Pathology and Laboratory Medicine
      Filadelfia, Pennsylvania, United States
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2012
    • University of Pennsylvania
      • Department of Physiology
      Filadelfia, Pennsylvania, United States