title: Inhibition of chaperone-mediated autophagy prevents glucotoxicity in the Caenorhabditis elegans mev-1 mutant by activation of the proteasome.
abstract: Chronic hyperglycemia is a hallmark of diabetes mellitus and the main cause of diabetes-associated complications. Increased intracellular glucose levels lead to damaged proteins and in consequence disturb cellular proteostasis. As an important contributor to the maintenance and restoration of proteostasis, autophagy mediates the lysosomal degradation of damaged proteins or entire cellular organelles. In the present study we used the stress-sensitive mev-1 mutant of the nematode Caenorhabditis elegans in order to assess the role of lmp-2, a homologue of the lysosome associated membrane protein type 2A, in the context of glucotoxicity, which was achieved by feeding glucose in a liquid medium. Knockdown of lmp-2 by RNA interference completely prevented the survival reduction caused by glucose under heat stress. Those effects were associated with the prevention of (1) increased lysosome formation and (2) reduction of proteasomal activity, which were observed under glucose feeding. Finally, the survival reduction due to knockdown of ubiquitin remained unaffected by the additional lmp-2 knockdown in the absence or presence of glucose. In conclusion, our study provides evidence that lmp-2, a key player in chaperone-mediated autophagy, is functional in C. elegans, too. Inhibition of lmp-2 prevents the reduction of proteasomal activity by glucose and thereby prevents also glucotoxicity.
authors.affiliation: Molecular Nutrition Research, Interdisciplinary Research Center, Justus Liebig University Gießen, Heinrich-Buff-Ring 26-32, D-35392, Gießen, Germany.
authors.forename: Dorothé Jenni
authors.initials: DJ
authors.lastname: Eisermann
authors.affiliation: Molecular Nutrition Research, Interdisciplinary Research Center, Justus Liebig University Gießen, Heinrich-Buff-Ring 26-32, D-35392, Gießen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wenzel
authors.affiliation: Molecular Nutrition Research, Interdisciplinary Research Center, Justus Liebig University Gießen, Heinrich-Buff-Ring 26-32, D-35392, Gießen, Germany. Electronic address: elena.fitzenberger@ernaehrung.uni-giessen.de.
authors.forename: Elena
authors.initials: E
authors.lastname: Fitzenberger
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000633:toxicity*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000502:physiology; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D029742:Caenorhabditis elegans Proteins; D017127:Glycation End Products, Advanced; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
keywords: Caenorhabditis elegans; Chaperone-mediated autophagy; Glucose; Proteasome; Proteostasis