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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

Analysis of institutional authors

Reglero-Real, NataliaAuthorBarroso, SusanaAuthorCorreas, IsabelAuthorCarazo, Jose-MariaAuthorMillan, JaimeCorresponding Author

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Article

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

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

Authors: 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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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. 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.

Keywords

ActinActin cytoskeletonActin filamentActomyosinAnimalsAntibody labelingApical membraneApicobasal polarityArticleAssociatioBile duct ligationBiotinylationBrush-borderCanalicular membraneCell adhesionCell adhesion moleculeCell biologyCell isolationCell polarityConfocal microscopyControlled studyCytoskeletonEbp50 proteinEbp50/nherf1/slc9a3r1ElectroporationEndoplasmic reticulumEndothelium cellEpithelial cellsExpression vectorFinite element analysisFluorescence microscopyGene editingGene silencingGenetic transfectionHepatocytesHumaHumanHuman cellHumansIcam-1ImmunoblottingImmunocompetent cellImmunocytochemistryImmunofluorescenceImmunofluorescence assayImmunohistochemistryImmunologyImmunoprecipitationImmunoreactivityInflammationIntercellular adhesion molecule 1Intercellular adhesion molecule-1Internalization (cell)Leukocyte adherenceLeukocytesLiverLiver organoidMass spectrometryMembrane proteinMiceMicrovilliMicrovillusMolecule-1MorphogenesisMouseMultidrug resistance associated protein 2Multidrug resistance protein 1Myosin adenosine triphosphataseMyosin heavy chainMyosin light chainNherf1 proteinNonhumanOligodendrogliaOrganoidPdz domainPhysiological stressProteinRho gtpasesScaffold proteinSignal noise ratioSlc9a3r1 proteinSmall interfering rnaStem-cellsThrombocyte structureTranscytosisTransmission electron microscopyUnclassified drugUpregulationVimentinWestern blotting

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal eLife due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 8/109, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biology. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-03:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 8.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 8 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 12.1.
  • The number of mentions on the social network X (formerly Twitter): 18 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/715014

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; United Kingdom.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Cacho-Navas, Cristina) and Last Author (MILLAN MARTINEZ, JAIME).

the author responsible for correspondence tasks has been MILLAN MARTINEZ, JAIME.