Abstract
Chemical modifications on histones constitute a key mechanism for gene regulation in chromatin context. Recently, histone lysine β-hydroxybutyrylation (Kbhb) was identified as a new form of histone acylation that connects starvation-responsive metabolism to epigenetic regulation. Sirtuins are a family of NAD+-dependent deacetylases. Through systematic profiling studies, we show that human SIRT3 displays class-selective histone de-β-hydroxybutyrylase activities with preference for H3 K4, K9, K18, K23, K27, and H4K16, but not for H4 K5, K8, K12, which distinguishes it from the Zn-dependent HDACs. Structural studies revealed a hydrogen bond-lined hydrophobic pocket favored for the S-form Kbhb recognition and catalysis. β-backbone but not side chain-mediated interactions around Kbhb dominate sequence motif recognition, explaining the broad site-specificity of SIRT3. The observed class-selectivity of SIRT3 is due to an entropically unfavorable barrier associated with the glycine-flanking motif that the histone Kbhb resides in. Collectively, we reveal the molecular basis for class-selective histone de-β-hydroxybutyrylation by SIRT3, shedding lights on the function of sirtuins in Kbhb biology through hierarchical deacylation.
Highlights
Posttranslational modifications (PTMs) on histones, often installed, recognized, and removed by their cognate “writers, readers, and erasers” in a type-specific and site-specific manner, play critical roles in regulating diverse chromatintemplated cellular processes[1,2]
Systematic profiling histone deacylase activities of sirtuins By means of click chemistry followed by affinity purification and competition assays, Bao et al revealed that SIRT3 is a histone decrotonylase and binds to H3K4 crotonylation (H3K4cr) peptide substrate at an affinity of ~25.1 μM in the absence of NAD+
The hydroxyl-replaced Khib and Kbhb marks are both recognized by SIRT3, SIRT5, and CobB; only Kbhb but not Khib can be recognized by SIRT1 and SIRT2 (Fig. 1c)
Summary
Posttranslational modifications (PTMs) on histones, often installed, recognized, and removed by their cognate “writers, readers, and erasers” in a type-specific and site-specific manner, play critical roles in regulating diverse chromatintemplated cellular processes[1,2]. Histone lysine acetylation (Kac) was firstly identified in early 1960s3, possessing a primary function in regulating gene transcription[4,5]. Extensive studies on the dynamic regulation and selective recognition of histone Kac have elucidated its role in various cellular regulatory mechanisms[6,7]. Histone lysine β-hydroxybutyrylation (Kbhb) has been detected in yeast, fly, mouse and human, and 44 Kbhb sites have been identified in human and mouse cells. It has been proposed that histone Kbhb directly connects ketone body metabolism to gene regulation, given the high concentration of β-hydroxybutyrate in blood during fasting, starvation, or prolonged intense exercise[15,18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
