Year: 2026
Type: preprint
Abstract: ABSTRACT RNAs are increasingly recognized as direct regulators of protein function, yet whether RNA can control the activation of signaling kinases remains poorly understood. Here we identify RNA as a direct regulator of BRAF, a central kinase in the RAS-RAF-MEK-ERK (MAPK) pathway. Using complementary crosslinking and RNA-protein interaction approaches, we show that BRAF directly binds RNA in cells and that this interaction is enhanced upon MAPK pathway activation. Depletion of intracellular RNA reduces BRAF:CRAF complex assembly and impairs MEK1/2 phosphorylation, indicating that RNA contributes to RAF complex formation and MAPK signal transduction. We identify a positively charged surface within the BRAF kinase domain that mediates RNA binding. A separation-of-function RNA-binding mutant selectively attenuates BRAF-dependent MEK1/2 phosphorylation, demonstrating that RNA binding is required for efficient MAPK signaling. Moreover, artificial recruitment of the RNA-binding-deficient BRAF mutant to an RNA scaffold restores its signaling activity, supporting a direct role for RNA-mediated BRAF complex assembly. These data identify RNA as an active component of RAF kinase regulation and establish RNA-protein interactions as an additional determinant of MAPK pathway activation.
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, Université Paris-Saclay, La Ligue Contre le Cancer, Intégrité du génome, ARN et cancer, Institut Curie, Institut Gustave Roussy, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut de Biologie Intégrative de la Cellule
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223350318