Quantitative chemoproteomics reveals O-GlcNAcylation of cystathionine γ-lyase (CSE) represses trophoblast syncytialization

Abstract

Emerging evidence indicates the involvement of O-GlcNAc modification in placental development and pregnant health through mechanisms that are not well understood. Herein, by applying the quantitative O-GlcNAc proteomics, we established a database of O-GlcNAcylated proteins in human placental trophoblasts. Hundreds of proteins that were dynamically O-GlcNAcylated during trophoblast differentiation were identified, among which cystathionine γ-lyase (CSE) exhibited the most significant change. Site-specific analysis by mass spectrometry revealed Ser¹³⁸ as the core O-GlcNAc site in CSE, and its O-GlcNAcylation promoted the enzymatic activity to produce H₂S, which in turn repressed trophoblast differentiation via inhibiting androgen receptor dimerization. Consistently, in preeclamptic placentas, remarkably enhanced CSE O-GlcNAcylation and H₂S production were associated with restricted trophoblast differentiation. The findings establish a resource of O-GlcNAc dynamics in human placenta, and provide a deeper insight into the biological significance of O-GlcNAcylation in placental development as well as potential therapeutic targets for the relevant pregnant complications.

Keywords: O-GlcNAcylation; androgen receptor; cystathionine γ-lyase; human trophoblast differentiation; preeclampsia.