Membrane Interaction Modulates RNA Secondary Structures and Phase Separation

To maintain homeostasis, cells utilize compartmentalization, traditionally achieved through membrane-bound organelles. However, recent discoveries have highlighted the importance of membrane-less compartments, known as biomolecular condensates (BCs), which form via liquid-liquid phase separation (LLPS). BCs, rich in nucleic acids and proteins, create distinct chemical environments that regulate key metabolic processes and can be temporally controlled. Dysregulation of BCs is linked to diseases such as cancer and neurodegeneration. Whilst the role of proteins in LLPS has been extensively studied, nucleic acids' contribution has been underexplored and attributed solely to electrostatic effects. More recently, it has been demonstrated that nucleic acid alone can drive phase separation, and G-quadruplex (G4), a non-canonical secondary structure, has been identified as a key element. G4s are formed in guanine-rich sequences and can act as crosslinking elements, promoting multivalent interactions required for LLPS. However, understanding the molecular mechanisms of RNA-driven phase separation remains incomplete. A key challenge is identifying mechanisms that reduce the critical concentration required for RNA-based phase separation, making models more biologically relevant. In MIMoSeS, I investigate the role of phospholipid membranes in promoting RNA condensation by selectively recruiting specific RNA secondary structures to their surface, thereby lowering the concentration needed for phase separation. While this mechanism is known for protein-based BCs, it is still underexplored for RNA. MIMoSeS will identify and describe the interplay of lipid membranes and RNA G-quadruplex structures as a putative mechanism for Liquid-Liquid Phase Separation and will provide new insights to study RNA biology from a fresh perspective.