PMC

Neuronal acetylation homeostasis. Pentagons on the balance beam represent the protein level (dose) of HATs and HDACs, while compasses represent their activity. Enzymatic activity within the green arc of the compass is physiologically optimum. (a) In neurons under normal conditions, the dose and activity of HATs and HDACs are poised in a fine balance where they counteract each other to ensure physiological homeostasis. (b) During neurodegeneration, critical loss of HAT protein level ensue a rebated HAT dose and activity. This reclines the acetylation balance towards excessive deacetylation of target moieties

Proposed model depicting central role of acetylation homeostasis during neurodegeneration: Various models and diseases of neurodegeneration are marked by critical loss of HAT. This loss, leading to acetylation imbalance, may be manifested by various means, which are employed singularly or in combination during a particular disease. Loss of acetylation homeostasis forms the last common port where several neurotoxic insults converge to mediate a self-demolishing neuronal response. Such responses include repression of prosurvival genes on the one hand and derepression of lethal genes on the other

Regulation of chromatin and prosurvival TFs by HATs and HDACs. HATs acetylate lysine residues on nucleosomal histones to render the chromatin accessible to the transcription machinery, which then upregulates the expression of an array of neurotrophic factors. HDACs reverse the process by histone deacetylation. Furthermore, HATs and HDACs also regulate the activity of certain prosurvival TFs (a–d). (a) CREB activity depends on its acetylation status. Phosphorylated CBP can acetylate CREB, which then undergoes conformational modification and forms a transactive dimer in association with the HAT. (b) The time and strength of NF-κB p65 : p50 is mediated by acetylation of p65 by HATs. However, if unphosphorylated, NF-κB p65 : p50 can interact with HDACs to form nontransactive complexes. Furthermore, p50 : p50 can form repressive complex with HDACs. (c) Hypoxic responses of HIF require steric interaction of HATs with HIF heterodimers. However, the probable enzymatic HAT activity is not yet reported. (d) Sp1 may conditionally interact with HATs or HDACs. Transactivation by Sp1 is accrued by its interaction with HATs and subsequent acetylation. (e) Nonepigenetic repression by HDAC. During HD, HDAC represses the expression of vital neuronal genes by forming a repressor complex with REST, which otherwise in normal conditions is arrested in the cytoplasm by wild huntingtin protein (Htt). Refer to the text for abbreviations

Signaling mechanisms for the activation of HAT and HDAC. (a) Pathways for the activation of CBP HAT in neurons. Activity-dependent activation of CBP depends on CAMK-IV-dependent phosphorylation on Ser 301. CBP is also activated by elevation in cAMP level. Ethanol, for example, phosphorylates adenosine A2 receptor by blocking adenosine uptake and its buildup. Subsequently, cAMP level is increased by adenylyl cyclase. cAMP-mediated activation of CBP is dependent on type-I PKA-mediated phosphorylation. Growth factors (like NGF) can trigger CBP phosphorylation via p42/p44 MAPK, which has been shown to interact directly with CBP. NGF can also trigger Ras pathway to mediate phosphorylation of 90 kDa ribosomal S6 kinase (RSK), which binds to CBP and canalizes expression of genes dependent on Ras pathway. However, this interaction inhibits expression of genes with CRE elements in PC12 cells. (b and c) Different modus operandi of class-I and class-II HDACs. HDAC1, HDAC2 and HDAC3 are phosphorylated by a distinct set of kinases. Once phosphorylated, they assemble into greater repressive complexes showing greater enzymatic activity and inhibit gene expression. In contrast, phosphorylation of HDAC8 decreases its enzymatic activity. Among all the represented HDAC complexes, the HDAC1/2-Co-REST complex is neuron specific. On the other hand, as shown in myoblasts, several type-II HDACs, once phosphorylated, are exported from the nucleus in complex with 14-3-3 proteins. The binding of HDACs with 14-3-3 proteins results in their release from the repression complex, allowing expression of the gene. Whether similar mechanisms are applicable to neurons is yet to be verified. Blue connectors represent kinase activity