HDAC8 substrates: Histones and beyond

Abstract

The lysine deacetylase family of enzymes (HDACs) was first demonstrated to catalyze deacetylation of acetyllysine residues on histones. In subsequent years, HDACs have been shown to recognize a large pool of acetylated non-histone proteins as substrates. Recently, thousands of acetylated proteins have been discovered, yet in most cases, the HDAC that catalyzes deacetylation in vivo has not been identified. This gap has created the need for better in vivo, in vitro, and in silico approaches for determining HDAC substrates. While HDAC8 is the best kinetically and structurally characterized HDAC, few efficient substrates have yet been substantiated in vivo. In this review we delineate factors that may be important for determining HDAC8 substrate recognition and catalytic activity, including structure, complex formation, and post-translational modifications. This summary provides insight into the challenges of identifying in vivo substrates for HDAC8, and provides a good vantage point for understanding the variables important for predicting HDAC substrate recognition.

HDAC8-Mediated Epigenetic Reprogramming Plays a Key Role in Resistance to Anthrax Lethal Toxin–Induced Pyroptosis in Macrophages

“…HDAC8 is constitutively active and widely expressed (33,39,40). To date, HDAC8 was shown to be involved in adenoviral E1A-12 protein-mediated gene suppression of the histocompatibility complex I genes (41) and transcriptional repression by the inversion-16 fusion gene products in acute myeloid leukemia cells (42).…”

HDAC8: a multifaceted target for therapeutic interventions

“…While overexpression may change the normal deacetylase activity, multiple washing in immunoprecipitation might wash away the substrate (if loosely associated) or might have other HDACs as contaminants (due to >30% similarity in aa sequences of class I HDACs [29,30]). Additionally, global acetylation modifications in histones might mask the specific deacetylation pattern of H3 by HDAC8.…”

Mechanism of N-Acylthiourea-mediated Activation of Human Histone Deacetylase 8 (HDAC8) at Molecular and Cellular Levels

“…Unlike other members of the class I HDACs, HDAC8 is known to interact with a limited number of proteins under in vivo conditions, although it is localized both in the nucleus and the cytosol (10,11). Interestingly, despite its nuclear localization, HDAC8 reportedly does not catalyze the deacetylation of acetyllysine moieties of histones under in vivo conditions.…”