Lysine succinylation precisely controls normal erythropoiesis.

Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemic, 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 knocking down key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylase SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identified 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies were observed between protein expression levels and succinylation levels, 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, regulation of erythropoiesis. Specifically, we identified CYCS as a key regulator of erythropoiesis, a function that 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 offers potential implications for erythroid-related diseases.