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.

中文翻译：

---

赖氨酸琥珀酰化精确控制正常的红细胞生成。


赖氨酸琥珀酰化 （Ksu） 最近作为一种蛋白质修饰出现，可调节各种生物过程中的不同功能。然而，赖氨酸琥珀酰化在红细胞生成中的系统性和精确作用仍有待完全阐明。在这项研究中，我们注意到在人红细胞分化过程中琥珀酰辅酶 A 和赖氨酸琥珀酰化显着增加。为了探索琥珀酰化的功能意义，我们通过敲除关键的琥珀酰转移酶或过表达脱琥珀酰化来抑制琥珀酰化。琥珀酰化抑制导致细胞增殖受到抑制，细胞凋亡增加，红细胞分化被破坏。脱硫素酶 SIRT5 的体内过表达延迟了红细胞分化。此外，整合蛋白质组和琥珀酸组分析鉴定了 939 种琥珀酰化蛋白，具有 3,562 个 Ksu 位点，分布在各个细胞区室并参与多个细胞过程。值得注意的是，观察到蛋白质表达水平和琥珀酰化水平之间的不一致，表明某些蛋白质的琥珀酰化可能独立于表达发挥作用。从机制上讲，我们涉及 KAT2A 介导的组蛋白 H3 K79 琥珀酰化，导致染色质重塑和随后的红细胞生成调节。特别是，我们确定 CYCS 是红细胞生成的关键调节因子，这取决于其琥珀酰化位点 K28/K40。综上所述，我们对红细胞生成过程中琥珀酰化景观的全面研究为其调节作用提供了有价值的见解，并为红细胞相关疾病提供了潜在影响。