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Agencia Estatal de Investigacion PID2020-119881RB-I00 Cristina Cacho-NavasCarmen Lopez-PujanteNatalia Colas-AlgoraSusana BarrosoGema de RivasJorge FeitoJaime MillanComunidad de Madrid P2022/BMD-7232 TomoXliver2 Ana CuervoSusana BarrosoJose-Maria CarazoJaime MillanComunidad de Madrid IND2019/BMD-17139 Jaime MillanAgencia Estatal de Investigacion PID2021-125386NB-I00 Carlo ManzoMarie Sklodowska-Curie Actions 608765 Natalia Reglero-RealAgencia Estatal de Investigacion PID2022-137552OA-I00 Natalia Reglero-RealAgencia Estatal de Investigacion RYC2021-031221-I Natalia Reglero-Real European Commission Regulation EU 2020/2094 Jaime MillanJose-Maria CarazoAna CuervoFondo Europeo de Desarrollo Regional PID2021-125386NB-I00 Carlo ManzoMinistry of Economy and Competitiveness FPI fellowship Cristina Cacho-NavasMinistry of Education, Culture and Sports FPU fellowship Natalia Colas-AlgoraFundacion Jimenez Diaz University Hospital Health Research Institute Endocornea Convenio Colaboracion CSIC Susana BarrosoThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication

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ICAM-1 nanoclusters regulate hepatic epithelial cell polarity by leukocyte adhesion-independent control of apical actomyosin

Publicado en:eLife. 12 RP89261- - 2024-04-10 12(), DOI: 10.7554/eLife.89261

Autores: Cacho-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.; Huch, M.; Millán, J.

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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.

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