Dynamic Changes in Lysine Succinylation As Important Regulators of Erythropoiesis

Abstract

Lysine succinylation has emerged as a recently discovered protein modification that significantly impacts the chemical environment and exhibits diverse functions in various biological processes. However, the specific role of lysine succinylation in erythropoiesis has not been fully elucidated. In this study, we investigated the levels of six common acylations (acetylation, crotonylation, succinylation, propionylation, butyrylation, and malonylation) in human erythroid cells. Interestingly, we observed a prominent accumulation of lysine succinylation during human erythroid differentiation, suggesting its potential importance in this process. To explore the functional significance of succinylation, we inhibited succinylation in human erythroid progenitor cell line by disrupting the expression of the key succinyltransferases and desuccinylases. The results revealed that succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted differentiation, indicating the essential role of succinylation in erythropoiesis. Furthermore, integrative proteome and succinylome analysis identifies 939 quantifiable proteins with 2,871 Ksu sites. Notably, we observed inconsistencies between alterations in protein levels and succinylation levels, suggesting that the role of succinylation in proteins' function regulation. These succinylated proteins are widely distributed in various cellular compartments and involved in multiple cell processes, indicating that succinylation is a prevalent modification in erythropoiesis. Mechanically, we identified CYCS as a key target of succinylation during erythropoiesis, emphasizing its essential role in this process. Specially, we implicated KAT2A-mediated histone succinylation in chromatin remodeling, further highlighting the regulatory significance of lysine succinylation in erythropoiesis at the epigenetic level. Collectively, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offer potential implications for erythroid-related diseases and therapeutic strategies.