title: Histone deacetylase 6 (HDAC6) plays a crucial role in p38MAPK-dependent induction of heme oxygenase-1 (HO-1) in response to proteasome inhibition.
abstract: The proteasome is responsible for the degradation of polyubiquitinated proteins. Inhibition of the proteasome leads to an accumulation of polyubiquitinated proteins and thus to an impairment of the cellular protein homeostasis. To prevent cellular damage on proteasome inhibition there is an up-regulation of several heat shock proteins (Hsps), including Hsp27, Hsp70, and heme oxygenase-1 (HO-1). It was demonstrated that the induction of classical Hsps, such as Hsp27 and Hsp70, is dependent on a HDAC6-dependent mechanism which releases HSF-1 and induces the expression of newly synthesized Hsps. In this study we demonstrate that the up-regulation of HO-1 on proteasome inhibition is mediated by p38MAPK and Nrf-2. Interestingly we found additional evidence, proving the involvement of HDAC6 in the up-regulation of HO-1. By using RNAi technologies against HDAC6 we demonstrate that there is a lack of the expected induction of HO-1, Nrf-2, and phosphorylated p38 (pp38) after proteasome inhibition. Furthermore, we can show that p38 is acetylated in unstressed cells and is a good substrate for HDAC6-mediated deacetylation. Therefore, we propose that on proteasome inhibition HDAC6 deacetylates p38, allowing the subsequent phosphorylation of p38 and resultant activation of NRF-2. NRF-2 enters the nucleus and functions as a transcription factor for HO-1.
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutrition, Friedrich-Schiller University Jena, Dornburger-Strasse 24, 07743 Jena, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Kästle
authors.forename: Esther
authors.initials: E
authors.lastname: Woschee
authors.forename: Tilman
authors.initials: T
authors.lastname: Grune
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
chemical_list: D018840:HSP70 Heat-Shock Proteins; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D061988:Proteasome Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; C067713:lactacystin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D044764:Ubiquitin-Activating Enzymes; C093642:SB 203580; D000111:Acetylcysteine