Co-Translational Deposition of N6-Acetyl-L-Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells

Dingyuan Guo; Nan Li; Xiaoyan Zhang; Runxin Zhou; Jie He; Xiao-Ping Ding; Weixing Yu; Fuqiang Tong; Sibi Yin; Yu Wang; Xin Xu; Long Wang; Mingzhu Fan; Shan Feng; Ke Liu; Ke Tang; Zhuqing Ouyang; Yusong R Guo; Yugang Wang

doi:10.1002/advs.202403309

Co-Translational Deposition of N⁶-Acetyl-L-Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells

Adv Sci (Weinh). 2024 Dec 4:e2403309. doi: 10.1002/advs.202403309. Online ahead of print.

Authors

Dingyuan Guo¹, Nan Li¹, Xiaoyan Zhang², Runxin Zhou¹, Jie He¹, Xiao-Ping Ding³, Weixing Yu¹, Fuqiang Tong¹, Sibi Yin¹, Yu Wang¹, Xin Xu⁴, Long Wang⁴, Mingzhu Fan^{5

6}, Shan Feng^{5

6}, Ke Liu⁷, Ke Tang¹, Zhuqing Ouyang², Yusong R Guo^{1

8}, Yugang Wang^{1

8}

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
² Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
³ Hubei Institute for Drug Control, Wuhan, Hubei, 430075, China.
⁴ School of Chemistry and Chemical Engineering and Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China.
⁵ Mass Spectrometry & Metabolomics Core Facility, The Biomedical Research Core Facility, Center for Research Equipment and Facilities, Westlake University, Hangzhou, Zhejiang, 310024, China.
⁶ Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China.
⁷ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250000, China.
⁸ Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.

PMID: 39630081
DOI: 10.1002/advs.202403309

Abstract

N⁶-acetyl-L-lysine residue is abundant in dietary protein but little is known about its potential influences on the diet-consumers. Herein, it is reported that Lysyl-tRNA synthetase (KARS) mediates co-translational deposition of diet-derived N⁶-acetyl-L-lysine (AcK) in nascent proteins to contribute to the acetylome in cells. Acetylated dietary protein is a direct source of AcK that can widely and substantially regulate the acetylome in multiple organs of mice. By analyzing the mechanisms underlying AcK contributing to the acetylome in mammalian cells, it is found that KARS can utilize AcK as an alternative substrate to produce N⁶-acetyl-l-lysyl-tRNA. The crystal structure of KARS in complex with AcK at 2.26 Å resolution shows that AcK shares the same substrate-binding pocket as L-lysine, allowed by a sidechain flip of Tyr499. The generated N⁶-acetyl-L-lysyl-tRNA introduces AcK into growing nascent polypeptide and results in protein acetylation, including the regions buried inside folded proteins that are post-translational modification (PTM)-inaccessible and functionally important. This undocumented protein modification mechanism is inherently different from PTM and termed as co-translational modification (coTM). It is expected to extend the repertoire of acetylome and improve the understanding of protein modification mechanisms in cells.

Keywords: KARS; co‐translational modification; protein acetylation.

Abstract

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