Lysine succinylation precisely controls normal erythropoiesis
Bin Hu,
Han Gong,
Ling Nie,
Ji Zhang,
Yanan Li,
Dandan Liu,
Huifang Zhang,
Haihang Zhang,
Lu Han,
Chaoying Yang,
Maohua Li,
Wenwen Xu,
Yukio Nakamura,
Lihong Shi,
Mao Ye,
Christopher D. Hillyer,
Narla Mohandas,
Long Liang,
Yue Sheng,
Jing Liu
Affiliations
Bin Hu
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Han Gong
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Ling Nie
Department of Hematology, Xiangya Hospital, Central South University, Hunan
Ji Zhang
The Affiliated Nanhua Hospital, Department of Clinical Laboratory, Hengyang Medical School, University of South China, Hunan
Yanan Li
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Dandan Liu
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Huifang Zhang
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Haihang Zhang
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Lu Han
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Chaoying Yang
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Maohua Li
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Wenwen Xu
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Yukio Nakamura
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki
Lihong Shi
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; CAMS Center for Stem Cell Medicine, PUMC Department of Stem Cell and Regenerative Medicine, Tianjin
Mao Ye
Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Hunan
Christopher D. Hillyer
Research Laboratory of Red Cell Physiology, New York Blood Center, New York
Narla Mohandas
Research Laboratory of Red Cell Physiology, New York Blood Center, New York
Long Liang
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Yue Sheng
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Jing Liu
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Hunan
Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemically and precise role of lysine succinylation in erythropoiesis remains to be fully elucidated. In this study, we noted a prominent increase of succinyl-CoA and lysine succinylation during human erythroid differentiation. To explore the functional significance of succinylation, we inhibited succinylation by either knock downing key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylases SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identifies 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies between protein expression levels and succinylation levels were observed, indicating that the succinylation of certain proteins may function independently of expression. Mechanistically, we implicated KAT2A-mediated succinylation of histone H3 K79, leading to chromatin remodeling and subsequently erythropoiesis regulation. Specially, we identified CYCS as a key regulator of erythropoiesis, which depends on its succinylation sites K28/K40. Taken together, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offer potential implications for erythroid-related diseases.
