Molecular Basis for Hierarchical Histone De-Β-Hydroxybutyrylation by Sirt3

Zhang, Xingrun; Cao, Ruili; Niu, Jinrong; Yang, Sen; Zhao, Shuai; Li, Haitao

doi:10.2139/ssrn.3231848

Cited by 16 publications

(28 citation statements)

References 57 publications

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“…Interestingly, the N-terminal peptide of H2B with modification at lysine 5 (H2BK5, 5 ) was poorly recognized by HDAC1–3. SIRT1–3, which have been shown to remove K( l -la) modifications from a pyruvate kinase M2 (PKM2) peptide to some extent ( 46 ), and Kbhb modifications from histone H3 peptides ( 47 ), only exhibited minor activity against the H3K18( l -la) ( 7b ) and H3K18( d -la) ( 7c ) peptides (Fig. 3D), in agreement with our initial screening data (Fig.…”

Section: Resultssupporting

confidence: 88%

“…Interestingly, both ε- N - d -β-hydroxybutyryllysine [K( d -bhb)] and ε- N -2-hydroxyisobutyryllysine (Khib) have been found on histones and connect cell metabolism with gene expression regulation ( 52, 53 ). Kbhb is also cleaved by SIRT1–3, although with lower efficiency in vitro ( 47 ). SIRT3 exhibits slight preference for K( l -bhb) over K( d -bhb) ( 47 ), whereas HDAC3 shows opposite selectivity (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Class I Histone Deacetylases (HDAC1–3) are Histone Lysine Delactylases

Moreno–Yruela

Wei

et al. 2021

Preprint

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Lysine L-lactylation (K(L-la)) is a newly discovered histone mark that can be stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylase enzymes remain unknown. Here, we report the systematic evaluation of zinc- and NAD+-dependent HDACs for their ability to cleave epsilon-N-L-lactyllysine marks. Our screens identified HDACs 1-3 and SIRT1-3 as delactylases in vitro. HDACs 1-3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Identification of p300 and HDAC3 as regulatory enzymes suggests that histone lactylation is installed and removed by enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway's regulatory elements.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Class I Histone Deacetylases (HDAC1–3) are Histone Lysine Delactylases

Moreno–Yruela

Wei

et al. 2021

Preprint

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“…The deacetylation of exclusively nuclear substrates also confirms the existence of nuclear SIRT3. Among the sirtuins, SIRT3 has the best ability to remove β -hydroxybutyryl (bhb) from the nuclear substrate H3K9bhb [63]. An additional nuclear substrate of SIRT3 is H3K56 [64].…”

Section: Resultsmentioning

confidence: 99%

The function of SIRT3 explored through the substrate interaction network

Nahálková

2020

Preprint

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SIRT3 is the mitochondrial protein lysine deacetylase with a prominent role in the maintenance of mitochondrial integrity vulnerable in the range of diseases. The present study examines the SIRT3 substrate interaction network for the identification of its biological functions in the cellular anti-aging mechanisms. The pathway enrichment, the protein function prediction, and the protein node prioritization analysis were performed based on 407 SIRT3 substrates, which were collected by the data mining. The substrates are interlinked by 1230 direct protein-protein interactions included in the GeneMania database. The analysis of the SIRT3 substrate interaction network highlighted Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and non-alcoholic fatty liver disease (NAFLD) as the most associated with SIRT3 lysine deacetylase activity. The most important biological functions of SIRT3 substrates are within the respiratory electron transport chain, tricarboxylic acid cycle and fatty acid, triacylglycerol, and ketone body metabolism. In brown adipose tissue, SIRT3 activity contributes to the adaptive thermogenesis by the increase of energy production of the organisms. SIRT3 exhibits several modes of neuroprotective actions in the brain and liver including prevention of the mitochondrial damages due to the respiratory electron transfer chain failure, the quenching of ROS, the inhibition of the mitochondrial membrane potential loss, and the regulation of mitophagy. Related to its role in Alzheimer’s disease, SIRT3 activation performs as a repressor of BACE1 through SIRT3-LKB1-AMPK-CREB-PGC-1α-PPARG-BACE1 (SIRT3-BACE1) pathway, which was created based on the literature mining and by employing Wikipathways application. The pathway enrichment analysis of the extended interaction network of the SIRT3-BACE1 pathway nodes displayed the functional relation to the circadian clock, which also deteriorates during the progress of AD and it is the causative of AD, PD, and HD. The use of SIRT3 activators in combination with the stimulating effect of regular exercise is further discussed as an attractive option for the improvement of cognitive decline during aging and the progressive stages of neurodegeneration.

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“…Although overwhelming studies indicate Sirt3 functions in the mitochondria due to its mitochondrial localization, a previous study shows that in humans, both the full‐length and processed forms of Sirt3 target H4‐K16 for deacetylation in vitro and can deacetylate H4‐K16 in vivo when recruited to a gene, and Sirt3 is transported from the nucleus to the mitochondria upon cellular stress (Scher, Vaquero, & Reinberg, 2007). A recent work with systematic study suggests that human Sirt3 displays class‐selective histone de‐β‐hydroxybutyrylase activities with preference for H3 K4, K9, K18, K23, K27, and H4 K16, but not for H4 K5, K8, and K12, which distinguishes it from HDACs, another group of deacetylation enzymes (Zhang et al, 2019). These reports suggest that Sirt3 is able to deacetylate proteins in the nucleus, not just in the mitochondria, albeit a transient nuclear presence for full‐length Sirt3.…”

Section: Discussionmentioning

confidence: 99%