Mice Lacking Histone Deacetylase 6 Have Hyperacetylated Tubulin but Are Viable and Develop Normally

Author:

Zhang Yu1,Kwon SoHee1,Yamaguchi Teppei1,Cubizolles Fabien1,Rousseaux Sophie2,Kneissel Michaela3,Cao Chun1,Li Na1,Cheng Hwei-Ling4,Chua Katrin4,Lombard David4,Mizeracki Adam1,Matthias Gabriele1,Alt Frederick W.4,Khochbin Saadi2,Matthias Patrick1

Affiliation:

1. Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, P.O. Box 2543, Maulbeerstrasse 66, 4058 Basel, Switzerland

2. INSERM U309, Institut Albert Bonniot, Faculté de Médecine, Domaine de la Merci, 38706 La Tronche Cedex, France

3. Novartis Institutes for Biomedical Research, Klybeckstrasse, Basel, Switzerland

4. Howard Hughes Medical Institute, The Children's Hospital, The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts 02115

Abstract

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, α-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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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