Identification of Histone Lysine Acetoacetylation as a Dynamic Post‐Translational Modification Regulated by HBO1

Author:

Gao Yan1,Sheng Xinlei2ORCID,Tan Doudou3ORCID,Kim SunJoo12ORCID,Choi Soyoung1,Paudel Sanjita1ORCID,Lee Taeho1ORCID,Yan Cong3,Tan Minjia3ORCID,Kim Kyu Min4,Cho Sam Seok5,Ki Sung Hwan5ORCID,Huang He36,Zhao Yingming2,Lee Sangkyu7ORCID

Affiliation:

1. College of Pharmacy Kyungpook National University Daegu 41566 Republic of Korea

2. Ben May Department for Cancer Research The University of Chicago Chicago IL 60637 USA

3. Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China

4. Department of Biomedical Science, College of Natural Science Chosun University Gwangju 61452 South Korea

5. College of Pharmacy Chosun University Gwangju 61452 South Korea

6. University of Chinese Academy of Sciences Beijing 100049 China

7. School of Pharmacy Sungkyunkwan University Suwon 16419 South Korea

Abstract

AbstractKetone bodies have long been known as a group of lipid‐derived alternative energy sources during glucose shortages. Nevertheless, the molecular mechanisms underlying their non‐metabolic functions remain largely elusive. This study identified acetoacetate as the precursor for lysine acetoacetylation (Kacac), a previously uncharacterized and evolutionarily conserved histone post‐translational modification. This protein modification is comprehensively validated using chemical and biochemical approaches, including HPLC co‐elution and MS/MS analysis using synthetic peptides, Western blot, and isotopic labeling. Histone Kacac can be dynamically regulated by acetoacetate concentration, possibly via acetoacetyl‐CoA. Biochemical studies show that HBO1, traditionally known as an acetyltransferase, can also serve as an acetoacetyltransferase. In addition, 33 Kacac sites are identified on mammalian histones, depicting the landscape of histone Kacac marks across species and organs. In summary, this study thus discovers a physiologically relevant and enzymatically regulated histone mark that sheds light on the non‐metabolic functions of ketone bodies.

Funder

National Research Foundation of Korea

University of Chicago

National Institutes of Health

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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