title: Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy.
abstract: The eukaryotic cell depends on multitiered homeostatic systems ensuring maintenance of proteostasis, organellar integrity, function and turnover, and overall cellular viability. At the two opposite ends of the homeostatic system spectrum are heat shock response and autophagy. Here, we tested whether there are interactions between these homeostatic systems, one universally operational in all prokaryotic and eukaryotic cells, and the other one (autophagy) is limited to eukaryotes. We found that heat shock response regulates autophagy. The interaction between the two systems was demonstrated by testing the role of HSF-1, the central regulator of heat shock gene expression. Knockdown of HSF-1 increased the LC3 lipidation associated with formation of autophagosomal organelles, whereas depletion of HSF-1 potentiated both starvation- and rapamycin-induced autophagy. HSP70 expression but not expression of its ATPase mutant inhibited starvation or rapamycin-induced autophagy. We also show that exercise induces autophagy in humans. As predicted by our in vitro studies, glutamine supplementation as a conditioning stimulus prior to exercise significantly increased HSP70 protein expression and prevented the expected exercise induction of autophagy. Our data demonstrate for the first time that heat shock response, from the top of its regulatory cascade (HSF-1) down to the execution stages delivered by HSP70, controls autophagy thus connecting and coordinating the two extreme ends of the homeostatic systems in the eukaryotic cell.
authors.affiliation: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Dokladny
authors.forename: Micah Nathaniel
authors.initials: MN
authors.lastname: Zuhl
authors.forename: Michael
authors.initials: M
authors.lastname: Mandell
authors.forename: Dhruva
authors.initials: D
authors.lastname: Bhattacharya
authors.forename: Suzanne
authors.initials: S
authors.lastname: Schneider
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
authors.forename: Pope Lloyd
authors.initials: PL
authors.lastname: Moseley
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D018938:Caco-2 Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D054878:Lipoylation / Q000187:drug effects / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D020123:Sirolimus
keywords: Akt; Autophagy; Exercise; Heat Shock Protein; Protein Folding; mTOR