Author(s): Carole Seidel aff1 , Michael Schnekenburger aff1 , Mario Dicato aff1 , Marc Diederich [*] aff2
autoimmune response; cancer; epigenetics; HDAC6; HDAC6 inhibitor; histone deacetylase; neurodegenerative disease
Acetylation of the ϵ nitrogen of lysine residues is catalyzed by histone acetyltransferases (HATs). Deacetylation of both nuclear proteins (including histones) and cytoplasmic proteins is catalyzed by histone deacetylases (HDACs).
In mammals, HATs are classified into two groups according to their cellular localization: group A is primarily nuclear, whereas group B is essentially cytoplasmic. A classification system using their sequence similarities is compromised by the lack of similarity between these enzymes. However, selected enzymes are classified according to their sequence similarity and function into the following families: GNAT (general control [GC]N5 related N -acetyltransferase), p300/CBP (cAMP response element-binding protein [CREB]-binding protein), MYST (MOZ, Ybf2/Sas3, SAS2 and TIP60), TAFII250 (TBP [TATA box binding protein]-associated factor 250 kDa) and steroid receptor cofactor (SRC) (for review, see [1 ]). All HAT enzymes use acetyl-coenzyme A as a cofactor.
There are 18 mammalian HDACs subdivided into four classes based on their sequence identity and catalytic activity (Figure 1). Indeed, classes I, II and IV are enzymes with a zinc ion at the bottom of their catalytic pocket essential for the deacetylation reaction; class III enzymes do not possess this ion, but their activity depends on the cofactor nicotinamide adenine dinucleotide (NAD+ ). Class I includes HDAC1, 2, 3 and 8, which are located mainly in the nucleus due to the presence of a nuclear localization signal (NLS). Interestingly, HDAC3 possesses also a nuclear export signal (NES) in the catalytic domain. Class II is divided into two subclasses: subclass IIa including HDAC4, 5, 7 and 9 and subclass IIb consisting of HDAC6 and 10. Class II isoenzymes possess a NLS as well as a NES except HDAC9 (NLS only) and HDAC10 (NES only). Class IV corresponds to HDAC11. Class III, also known as sirtuins by analogy with yeast silent information regulator 2 (SIR2), contains seven members, SIRT1 to 7; some members contain NES and/or NLS (for review, see [2 ]).
HDAC6 is the only isoenzyme of the HDAC family with two functional active sites. This enzyme presents specific protein domains (from N- terminal to C-terminal): a NLS rich in arginine and lysine sequences; a leucine-rich NES; catalytic sites 1 and 2; a cytoplasmic retention signal called SE14, which is a repeated sequence of eight consecutive Ser-Glu tetradecapeptides is present in human but absent in mouse, Drosophila and Caenorhabditis elegans and a zinc finger ubiquitin binding domain (BUZ, Figure 1) (for review, see [3-5 ]). HDAC6 activity is regulated by post-translational modifications: kinases such as Aurora A, extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3[beta] (GSK), G protein-coupled receptor kinase 2 (GRK), protein kinase C [alpha] (PKC), epidermal growth factor receptor (EGFR) or casein kinase 2 (CK) phosphorylate HDAC6 on threonines (T868, T30, T1031), serines (S22, S458, S846, S847, S1035 and S1062) and tyrosine Y570 leading to increased deacetylase activity [6,7 ]. In addition, various lysines (K36,...