Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally.
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.
Zhang
Yu
Y
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, P.O. Box 2543, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Kwon
Sohee
S
Yamaguchi
Teppei
T
Cubizolles
Fabien
F
Rousseaux
Sophie
S
Kneissel
Michaela
M
Cao
Chun
C
Li
Na
N
Cheng
Hwei-Ling
HL
Chua
Katrin
K
Lombard
David
D
Mizeracki
Adam
A
Matthias
Gabriele
G
Alt
Frederick W
FW
Khochbin
Saadi
S
Matthias
Patrick
P
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*
D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D014404:Tubulin; D049410:Luciferases, Renilla; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases