GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Heparan sulfate proteoglycans (HSPGs) are crucial co-receptors for growth factors like VEGF-A, mediating cell signaling.
• The precise mechanisms by which HSPGs regulate cell surface signaling, especially with cell surface RNA, are not well understood.
• VEGF-A signaling is vital for endothelial cell growth and angiogenesis, with regulation often attributed to heparan sulfate chain sulfation.

Purpose of the Study:

• To investigate the organizational rules of cell surface conjugates, specifically glycoRNAs and cell surface RNA-binding proteins (csRBPs).
• To elucidate the mechanistic role of HSPGs and cell surface ribonucleoproteins (csRNPs) in regulating VEGF-A signaling.
• To uncover novel regulatory pathways influencing angiogenesis.

Main Methods:

• Genome-scale knockout screens to identify genes critical for csRNP assembly.
• Biochemical assays to determine the interaction between VEGF-A, RNA, and heparan sulfate.
• In vitro and in vivo studies using model systems to assess the impact on vascular development.

Main Results:

• Heparan sulfate biosynthesis, particularly 6-O-sulfation, is essential for the assembly of glycoRNA and csRBP clusters (csRNPs).
• These csRNP clusters antagonize ERK signaling activation downstream of VEGF-A.
• The VEGF-A binding domain is responsible for RNA interaction; disrupting this interaction enhances ERK signaling and impairs vascular development.

Conclusions:

• Cell surface ribonucleoproteins (csRNPs) represent a novel class of anionic cell surface conjugates.
• csRNPs negatively regulate heparan sulfate-mediated signaling pathways, specifically impacting VEGF-A-driven angiogenesis.
• This interaction between VEGF-A, RNA, and heparan sulfate presents a previously unrecognized regulatory axis in vascular development.