title: Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally.
abstract: Posttranslational modifications play important roles in regulating protein structure and function. Histone deacetylase 6 (HDAC6) is a mostly cytoplasmic class II HDAC, which has a unique structure with two catalytic domains and a domain binding ubiquitin with high affinity. This enzyme was recently identified as a multisubstrate protein deacetylase that can act on acetylated histone tails, alpha-tubulin and Hsp90. To investigate the in vivo functions of HDAC6 and the relevance of tubulin acetylation/deacetylation, we targeted the HDAC6 gene by homologous recombination in embryonic stem cells and generated knockout mice. HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues. The highest level of expression of HDAC6 is seen in the testis, yet development and function of this organ are normal in the absence of HDAC6. Likewise, lymphoid development is normal, but the immune response is moderately affected. Furthermore, the lack of HDAC6 results in a small increase in cancellous bone mineral density, indicating that this deacetylase plays a minor role in bone biology. HDAC6-deficient mouse embryonic fibroblasts show apparently normal microtubule organization and stability and also show increased Hsp90 acetylation correlating with impaired Hsp90 function. Collectively, these data demonstrate that mice survive well without HDAC6 and that tubulin hyperacetylation is not detrimental to normal mammalian development.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, P.O. Box 2543, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sohee
authors.initials: S
authors.lastname: Kwon
authors.forename: Teppei
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Fabien
authors.initials: F
authors.lastname: Cubizolles
authors.forename: Sophie
authors.initials: S
authors.lastname: Rousseaux
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
authors.forename: Chun
authors.initials: C
authors.lastname: Cao
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: Katrin
authors.initials: K
authors.lastname: Chua
authors.forename: David
authors.initials: D
authors.lastname: Lombard
authors.forename: Adam
authors.initials: A
authors.lastname: Mizeracki
authors.forename: Gabriele
authors.initials: G
authors.lastname: Matthias
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
mesh_terms: D015502:Absorptiometry, Photon; D000107:Acetylation; D000818:Animals; D015519:Bone Density / Q000235:genetics; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D005328:Fetal Viability / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000172:deficiency* / Q000235:genetics; D006720:Homozygote; D007150:Immunohistochemistry; D049410:Luciferases, Renilla / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011233:Precipitin Tests; D011247:Pregnancy; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011995:Recombination, Genetic; D013076:Sperm Count; D013091:Spermatogenesis; D013737:Testis / Q000166:cytology / Q000201:enzymology; D014162:Transfection; D014404:Tubulin / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D014404:Tubulin; D049410:Luciferases, Renilla; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases