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Targeting EDEM protects against ER stress and improves development and survival in C. elegans
Authors:Simona Ghenea  Marioara Chiritoiu  Robi Tacutu  Antonio Miranda-Vizuete  Stefana Maria Petrescu
Affiliation:1. Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania;2. Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry, Romanian Academy, Bucharest, Romania;3. Redox Homeostasis Group, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain; The University of Texas Health Science Center at Houston, UNITED STATES
Abstract:EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival.
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