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

Author:

Cacho-Navas Cristina1,López-Pujante Carmen1,Reglero-Real Natalia2,Colás-Algora Natalia1,Cuervo Ana3,Conesa José Javier3,Barroso Susana1,Rivas Gema de1,Ciordia Sergio3,Paradela Alberto3,D’Agostino Gianluca3,Manzo Carlo4,Feito Jorge5,Andrés Germán1,Molina-Jiménez Francisca67,Majano Pedro6789,Correas Isabel1,Carazo Jose María3,Nourshargh Sussan2,Huch Meritxell10,Millán Jaime1

Affiliation:

1. Centro de Biología Molecular Severo Ochoa, CSIC-UAM

2. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London

3. Centro Nacional de Biotecnología, CSIC

4. Facultat de Ciències, Tecnologia i Enginyeries, Universitat de Vic – Universitat Central de Catalunya (UVic-UCC)

5. Servicio de Anatomía Patológica, Hospital Universitario de Salamanca

6. Molecular Biology Unit, Hospital Universitario de la Princesa

7. Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa)

8. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)

9. Department of Cellular Biology, Faculty of Biology, Universidad Complutense de Madrid

10. Max Planck Institute of Molecular Cell Biology and Genetics

Abstract

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 (BCs). 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.

Publisher

eLife Sciences Publications, Ltd

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