Microtubules are cylindrical cytoskeletal structures found in almost all eukaryotic cell types which are involved in a great variety of cellular processes. Reversible acetylation on the ϵ‐amino group of α‐tubulin Lys40 marks stabilized microtubule structures and may contribute to regulating microtubule dynamics. Yet, the enzymes catalysing this acetylation/deacetylation have remained unidentified until recently. Here we report that β‐tubulin interacts with histone deacetylase‐6 (HDAC‐6) in a yeast two‐hybrid assay and in vitro. We find that HDAC‐6 is a micro tubule‐associated protein capable of deacetylating α‐tubulin in vivo and in vitro. HDAC‐6's microtubule binding and deacetylation functions both depend on the hdac domains. Overexpression of HDAC‐6 in mammalian cells leads to tubulin hypoacetylation. In contrast, inhibition of HDAC‐6 function by two independent mechanisms—pharmacological (HDAC inhibitors) or genetic (targeted inactivation of HDAC‐6 in embryonic stem cells)—leads to hyperacetylation of tubulin and microtubules. Taken together, our data provide evidence that HDAC‐6 might act as a dual deacetylase for tubulin and histones, and suggest the possibility that acetylated non‐histone proteins might represent novel targets for pharmacological therapy by HDAC inhibitors.

A cellular defense mechanism counteracts the deleterious effects of misfolded protein accumulation by eliciting a stress response. The cytoplasmic deacetylase HDAC6 (histone deacetylase 6) was previously shown to be a key element in this response by coordinating the clearance of protein aggregates through aggresome formation and their autophagic degradation. Here, for the first time, we demonstrate that HDAC6 is involved in another crucial cell response to the accumulation of ubiquitinated protein aggregates, and unravel its molecular basis. Indeed, our data show that HDAC6 senses ubiquitinated cellular aggregates and consequently induces the expression of major cellular chaperones by triggering the dissociation of a repressive HDAC6/HSF1 (heat-shock factor 1)/HSP90 (heat-shock protein 90) complex and a subsequent HSF1 activation. HDAC6 therefore appears as a master regulator of the cell protective response to cytotoxic protein aggregate formation.[Keywords: HSP25/27; HSP70; acetylation; microtubules; heat shock; p97/VCP] Supplemental material is available at http://www.genesdev.org.

During male germ cell postmeiotic maturation, dramatic chromatin reorganization occurs, which is driven by completely unknown mechanisms. For the first time, we describe a specific reprogramming of mouse pericentric heterochromatin. Initiated when histones undergo global acetylation in early elongating spermatids, this process leads to the establishment of new DNA packaging structures organizing the pericentric regions in condensing spermatids. Five new histone variants were discovered, which are expressed in late spermiogenic cells. Two of them, which we named H2AL1 and H2AL2, specifically mark the pericentric regions in condensing spermatids and participate in the formation of new nucleoprotein structures. Moreover, our investigations also suggest that TH2B, an already identified testis-specific H2B variant of unknown function, could provide a platform for the structural transitions accompanying the incorporation of these new histone variants.