Cacho Navas, CristinaLópez Pujante, CarmenReglero Real, NataliaColás Algora, NataliaCuervo, AnaConesa, Jose JavierBarroso, Susanade Rivas, GemaCiordia, SergioParadela, AlbertoD'Agostino, GianlucaManzo, CarloFeito, JorgeAndrés, GermánMolina Jiménez, FranciscaMajano Rodríguez, Pedro LorenzoCorreas, IsabelCarazo, José MariaNourshargh, SussanHuch, MeritxellMillán, Jaime2025-03-262025-03-262024Cacho-Navas, C., López-Pujante, C., Reglero-Real, N., Colás-Algora, N., Cuervo, A., Conesa, J. J., Barroso, S., De Rivas, G., Ciordia, S., Paradela, A., D’Agostino, G., Manzo, C., Feito, J., Andrés, G., Molina-Jiménez, F., Majano, P., Correas, I., Carazo, J.-M., Nourshargh, S., … Millán, J. (2024). ICAM-1 nanoclusters regulate hepatic epithelial cell polarity by leukocyte adhesion-independent control of apical actomyosin. eLife, 12, RP89261. https://doi.org/10.7554/eLife.89261.32050-084X10.7554/elife.89261.3https://hdl.handle.net/20.500.14352/118973Financiación: Agencia Estatal de Investigación (PID2020-119881RB-I00), Comunidad de Madrid (P2022/BMD-7232 TomoXliver2), Comunidad de Madrid (IND2019/BMD-17139), Agencia Estatal de Investigación (PID2021-125386NB-I00), Marie Skłodowska-Curie Actions (608765), Agencia Estatal de Investigación (PID2022-137552OA-I00), Agencia Estatal de Investigación (RYC2021-031221-I), European Commission (Regulation EU 2020/2094), Fondo Europeo de Desarrollo Regional (PID2021-125386NB-I00), Ministry of Economy and Competitiveness (FPI fellowship), Ministry of Education, Culture and Sports (FPU fellowship), Fundación Jiménez Díaz University Hospital Health Research Institute (Endocornea Convenio Colaboración CSIC)Epithelial intercellular adhesion molecule (ICAM)-1 is apically polarized, interacts with, and guides leukocytes across epithelial barriers. Polarized hepatic epithelia organize their apical membrane domain into bile canaliculi and ducts, which are not accessible to circulating immune cells but that nevertheless confine most of ICAM-1. Here, by analyzing ICAM-1_KO human hepatic cells, liver organoids from ICAM-1_KO mice and rescue-of-function experiments, we show that ICAM-1 regulates epithelial apicobasal polarity in a leukocyte adhesion-independent manner. ICAM-1 signals to an actomyosin network at the base of canalicular microvilli, thereby controlling the dynamics and size of bile canalicular-like structures. We identified the scaffolding protein EBP50/NHERF1/SLC9A3R1, which connects membrane proteins with the underlying actin cytoskeleton, in the proximity interactome of ICAM-1. EBP50 and ICAM-1 form nano-scale domains that overlap in microvilli, from which ICAM-1 regulates EBP50 nano-organization. Indeed, EBP50 expression is required for ICAM-1-mediated control of BC morphogenesis and actomyosin. Our findings indicate that ICAM-1 regulates the dynamics of epithelial apical membrane domains beyond its role as a heterotypic cell–cell adhesion molecule and reveal potential therapeutic strategies for preserving epithelial architecture during inflammatory stress.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.7554/eLife.89261.3https://elifesciences.org/articles/89261open access576.3577.1612.35Biología molecular (Biología)Biología celular (Biología)Bioquímica (Biología)Fisiología2415 Biología Molecular2407 Biología Celular2403 Bioquímica2401.04 Citología Animal32 Ciencias Médicas