title: Activation of autophagy by unfolded proteins during endoplasmic reticulum stress.
abstract: Endoplasmic reticulum stress is defined as the accumulation of unfolded proteins in the endoplasmic reticulum, and is caused by conditions such as heat or agents that cause endoplasmic reticulum stress, including tunicamycin and dithiothreitol. Autophagy, a major pathway for degradation of macromolecules in the vacuole, is activated by these stress agents in a manner dependent on inositol-requiring enzyme 1b (IRE1b), and delivers endoplasmic reticulum fragments to the vacuole for degradation. In this study, we examined the mechanism for activation of autophagy during endoplasmic reticulum stress in Arabidopsis thaliana. The chemical chaperones sodium 4-phenylbutyrate and tauroursodeoxycholic acid were found to reduce tunicamycin- or dithiothreitol-induced autophagy, but not autophagy caused by unrelated stresses. Similarly, over-expression of BINDING IMMUNOGLOBULIN PROTEIN (BIP), encoding a heat shock protein 70 (HSP70) molecular chaperone, reduced autophagy. Autophagy activated by heat stress was also found to be partially dependent on IRE1b and to be inhibited by sodium 4-phenylbutyrate, suggesting that heat-induced autophagy is due to accumulation of unfolded proteins in the endoplasmic reticulum. Expression in Arabidopsis of the misfolded protein mimics zeolin or a mutated form of carboxypeptidase Y (CPY*) also induced autophagy in an IRE1b-dependent manner. Moreover, zeolin and CPY* partially co-localized with the autophagic body marker GFP-ATG8e, indicating delivery to the vacuole by autophagy. We conclude that accumulation of unfolded proteins in the endoplasmic reticulum is a trigger for autophagy under conditions that cause endoplasmic reticulum stress.
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 50011, USA.|Interdepartmental Plant Biology Program, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Yang
authors.affiliation: Plant Sciences Institute, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 50011, USA.|Interdepartmental Plant Biology Program, Iowa State University, Ames, IA, 50011, USA.|Plant Sciences Institute, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Howell
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 50011, USA.|Interdepartmental Plant Biology Program, Iowa State University, Ames, IA, 50011, USA.|Plant Sciences Institute, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Bassham
mesh_terms: D017360:Arabidopsis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D058767:Protein Unfolding; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014415:Tunicamycin / Q000494:pharmacology; D014617:Vacuoles / Q000378:metabolism
chemical_list: D010654:Phenylbutyrates; D014415:Tunicamycin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D004229:Dithiothreitol
keywords: Arabidopsis thaliana; autophagy; degradation; endoplasmic reticulum stress; unfolded proteins; vacuole; zeolin