RNA-binding proteins and glycoRNAs form domains on the cell surface for cell-penetrating peptide entry. Cell. 2025 Apr 03; 188(7):1878-1895.e25.

Citation

Perr J, Langen A, Almahayni K, Nestola G, Chai P, Lebedenko CG, Volk RF, Detrés D, Caldwell RM, Spiekermann M, Hemberger H, Bisaria N, Aiba T, Sánchez-Rivera FJ, Tzelepis K, Calo E, Möckl L, Zaro BW, Flynn RA. 2025. RNA-binding proteins and glycoRNAs form domains on the cell surface for cell-penetrating peptide entry. Cell. 188(7):1878-1895.e25. Pubmed: 40020667 DOI:S0092-8674(25)00109-6

Abstract

The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA-binding proteins (RBPs) is present on the surface of living cells. These cell-surface RBPs (csRBPs) precisely organize into well-defined nanoclusters enriched for multiple RBPs and glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell-surface interaction for the cell-penetrating peptide trans-activator of transcription (TAT). Removal of RNA from the cell surface, or loss of RNA-binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.

Related Faculty

Ryan Flynn, M.D., Ph.D.

Flynn Lab

Ryan Flynn’s laboratory is focused on the exploration and discovery of how biopolymers like RNA and glycans work together to control cellular processes in the context of human disease.