title: Histone deacetylase 6 associates with ribosomes and regulates de novo protein translation during arsenite stress.
abstract: Histone deacetylase 6 (HDAC6) is known as a cytoplasmic enzyme that regulates cell migration, cell adhesion, and degradation of misfolded proteins by deacetylating substrates such as α-tubulin and Hsp90. When HaCaT keratinocytes were exposed to 1-200μM sodium arsenite, we observed perinuclear localization of HDAC6 within 30 min. Although the overall level of HDAC6 protein did not change, sodium arsenite caused an increase of HDAC6 in ribosomal fractions. Separation of ribosomal subunits versus intact ribosomes or polysomes indicated that HDAC6 was mainly detected in 40/43S fractions containing the small ribosomal subunit in untreated cells but was associated with 40/43S and 60/80S ribosomal fractions in arsenite-treated cells. Immunocytochemistry studies revealed that arsenite caused colocalization of HDAC6 with the ribosomal large and small subunit protein L36a and S6. Both L36a and S6 were detected in the immunocomplex of HDAC6 isolated from arsenite-treated cells. The observed physical interaction of HDAC6 with ribosomes pointed to a role of HDAC6 in stress-induced protein translation. Among arsenite stress-induced proteins, de novo Nrf2 protein translation was inhibited by Tubastatin A. These data demonstrate that HDAC6 was recruited to ribosomes, physically interacted with ribosomal proteins, and regulated de novo protein translation in keratinocytes responding to arsenite stress.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Kyle V
authors.initials: KV
authors.lastname: Kappeler
authors.forename: Jack
authors.initials: J
authors.lastname: Zhang
authors.forename: Thai Nho
authors.initials: TN
authors.lastname: Dinh
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Strom
authors.forename: Qin M
authors.initials: QM
authors.lastname: Chen
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D038601:Ribosomal Protein S6 / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: D018053:Arsenites; D004785:Environmental Pollutants; C489129:RPL36A protein, human; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D017670:Sodium Compounds; C017947:sodium arsenite; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases