title: Herp depletion protects from protein aggregation by up-regulating autophagy.
abstract: Herp is an endoplasmic reticulum (ER) stress inducible protein that participates in the ER-associated protein degradation (ERAD) pathway. However, the contribution of Herp to other protein degradation pathways like autophagy and its connection to other types of stress responses remain unknown. Here we report that Herp regulates autophagy to clear poly-ubiquitin (poly-Ub) protein aggregates. Proteasome inhibition and glucose starvation (GS) led to a high level of poly-Ub protein aggregation that was drastically reduced by stably knocking down Herp (shHerp cells). The enhanced removal of poly-Ub inclusions protected cells from death caused by glucose starvation. Under basal conditions and increasingly after stress, higher LC3-II levels and GFP-LC3 puncta were observed in shHerp cells compared to control cells. Herp knockout cells displayed basal up-regulation of two essential autophagy regulators-Atg5 and Beclin-1, leading to increased autophagic flux. Beclin-1 up-regulation was due to a reduction in Hrd1 dependent proteasomal degradation, and not at transcriptional level. The consequent higher autophagic flux was necessary for the clearance of aggregates and for cell survival. We conclude that Herp operates as a relevant factor in the defense against glucose starvation by modulating autophagy levels. These data may have important implications due to the known up-regulation of Herp in pathological states such as brain and heart ischemia, both conditions associated to acute nutritional stress.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile; Harvard School of Public Health, Boston, MA, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Quiroga
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Damian
authors.initials: D
authors.lastname: Gatica
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Paredes
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Zully
authors.initials: Z
authors.lastname: Pedrozo
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Rodriguez
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Barbra
authors.initials: B
authors.lastname: Toro
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile; The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK.
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380492, Chile; The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK. Electronic address: chetz@hsph.harvard.edu.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS) & Center for Molecular Studies of the Cell, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380492, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: slavander@uchile.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D025821:Polyubiquitin / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020836:Protein Structure, Quaternary; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C485932:HERPUD1 protein, human; D008565:Membrane Proteins; D061988:Proteasome Inhibitors; D025821:Polyubiquitin; D005947:Glucose
keywords: Autophagy; Beclin-1; Endoplasmic reticulum stress; Poly-ubiquitinated protein; Protein aggregation; UPR