Phosphoproteomic Landscape of HDLBP: Insights into Function and Disease Associations

TL;DR

This paper maps the phosphorylation sites of HDLBP, revealing how specific modifications may regulate its roles in RNA metabolism, cell cycle, and cancer.

Contribution

The study provides the first integrated phosphoproteomic analysis of HDLBP, identifying site-specific regulatory networks and disease associations.

Findings

Phosphorylation sites S31 and S944 of HDLBP are co-phosphorylated and linked to RNA metabolism and cell cycle regulation.

Site-specific phospho-regulation of HDLBP is associated with apoptosis, carcinogenesis, and lipid homeostasis.

Differential phosphorylation of HDLBP across cancers suggests roles in tumor-associated pathways.

Abstract

High-density lipoprotein-binding protein (HDLBP), also called Vigilin, is a multifunctional RNA-binding protein with established roles in RNA transport and regulation, chromosome segregation, lipid homeostasis, and translational regulation. Frequently detected to be perturbed in phosphoproteome analysis, phosphorylation is indicated as a major mechanism in the regulation of HDLBP functions; however, its phosphorylation landscape remains unexplored. We performed a meta-phosphoproteome analysis of HDLBP to map site-specific functional and regulatory roles of its two most frequently detected phosphosites, S31 and S944. Co-occurrence analysis across multiple datasets indicated that they can be phosphorylated together, suggesting potential co-ordinated regulation. Site-specific co-regulation analysis revealed distinct phospho-regulatory networks, with upstream kinases identified exclusively for S944. Functional enrichment of co-regulated protein phosphosites (CPPs) highlighted its role in RNA metabolism, chromosome organization, and nucleoplasmic transport, while functional annotation of site-specific phosphorylation of CPPs indicates its involvement in cell cycle regulation, apoptosis, and carcinogenesis. Additionally, the potential role of CPPs in the lipid homeostasis network was explored. Furthermore, the differential expression of HDLBP phosphosites across multiple cancers was observed using UALCAN, suggesting a potential role for phospho-regulation of HDLBP in tumor-associated pathways. Together, these findings provide the first integrated view of HDLBP phosphorylation and could serve as a valuable framework for future targeted studies to elucidate the mechanistic roles of site-specific HDLBP phosphorylation in cellular and pathophysiological processes.

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