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A Novel PLEKHA7 Interactor at Adherens Junctions

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A Novel PLEKHA7 Interactor at Adherens Junctions Thesis PDZD11: a novel PLEKHA7 interactor at adherens junctions GUERRERA, Diego Abstract PLEKHA7 is a recently identified protein of the AJ that has been involved by genetic and genomic studies in the regulation of miRNA signaling and cardiac contractility, hypertension and glaucoma. However, the molecular mechanisms behind PLEKHA7 involvement in tissue physiology and pathology remain unknown. In my thesis I report novel results which uncover PLEKHA7 functions in epithelial and endothelial cells, through the identification of a novel molecular interactor of PLEKHA7, PDZD11, by yeast two-hybrid screening, mass spectrometry, co-immunoprecipitation and pulldown assays. I dissected the structural basis of their interaction, showing that the WW domain of PLEKHA7 binds to the N-terminal region of PDZD11; this interaction mediates the junctional recruitment of PDZD11, identifying PDZD11 as a novel AJ protein. I provided evidence that PDZD11 forms a complex with nectins at AJ, its PDZ domain binds to the PDZ-binding motif of nectins. PDZD11 stabilizes nectins promoting the early steps of junction assembly. Reference GUERRERA, Diego. PDZD11: a novel PLEKHA7 interactor at adherens junctions. Thèse de doctorat : Univ. Genève, 2016, no. Sc. 4962 URN : urn:nbn:ch:unige-877543 DOI : 10.13097/archive-ouverte/unige:87754 Available at: http://archive-ouverte.unige.ch/unige:87754 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENÈVE FACULTE DES SCIENCES Section de Biologie Prof. Sandra Citi Département de Biologie Cellulaire PDZD11: a novel PLEKHA7 interactor at adherens junctions THÈSE Présentée à la Faculté des sciences de l’Université de Genève Pour obtenir le grade de Doctor ès science, mention Biologie par DIEGO GUERRERA de Benevento (Italie) Thèse N° 4962 GENÈVE Atelier d'impression Repromail 2016 1 Table of contents RÉSUMÉ ................................................................................................................... 4 ABSTRACT .............................................................................................................. 6 INTRODUCTION ....................................................................................................... 8 TIGHT JUNCTIONS (TJ) ..................................................................................... 10 Transmembrane proteins ................................................................................. 12 Cytoplasmic proteins ....................................................................................... 14 Cingulin ..................................................................................................................................... 17 Paracingulin .............................................................................................................................. 19 ADHERENS JUNCTIONS (AJ) ............................................................................ 21 Cadherins ........................................................................................................ 23 E-cadherin ....................................................................................................... 24 Nectins ............................................................................................................ 26 Catenins .......................................................................................................... 28 a-catenin ................................................................................................................................... 29 b-catenin ................................................................................................................................... 30 p120-catenin ............................................................................................................................. 31 Afadin .............................................................................................................. 33 PLEKHA7 ........................................................................................................ 34 REGULATION OF JUNCTION FORMATION AND STABILITY ............................ 37 ZONULAR PROTEINS: THE MOLECULAR LINKAGE BETWEEN AJ AND TJ .... 41 RESEARCH PROJECT ....................................................................................... 42 PAPERS ................................................................................................................. 44 PLEKHA7 MODULATES EPITHELIAL TIGHT JUNCTION BARRIER FUNCTION .................. 45 MGCRACGAP INTERACTS WITH CINGULIN AND PARACINGULIN TO REGULATE RAC1 ACTIVATION AND DEVELOPMENT OF THE TIGHT JUNCTION BARRIER DURING EPITHELIAL JUNCTION ASSEMBLY ............................................................................................. 47 2 THE ADHERENS JUNCTIONS CONTROL SUSCEPTIBILITY TO STAPHYLOCOCCUS AUREUS a-TOXIN ................................................................................................................ 49 PLEKHA7 RECRUITS PDZD11 TO ADHERENS JUNCTIONS TO STABILIZE NECTINS ...... 51 EPITHELIAL JUNCTIONS AND RHO FAMILY GTPASES: THE ZONULAR SIGNALOSOME .... 53 PLEKHA7: CYTOSKELETAL ADAPTOR PROTEIN AT CENTER STAGE IN JUNCTIONAL ORGANIZATION AND SIGNALING .............................................................................. 54 DISCUSSION AND PERSPECTIVES ..................................................................... 55 REFERENCES ........................................................................................................ 72 3 Résumé Les cellules épithéliales fournissent une barrière entre les environnements externe et interne du corps et définissent une compartimentation tissulaire dans les organes, en recouvrant toutes les surfaces et les cavités internes du corps. Les cellules épithéliales polarisées des vertébrés sont caractérisées par un complexe jonctionnel comprenant les jonctions serrées, les jonctions adhérentes et les desmosomes. Le complexe jonctionnel est responsable de l’adhésion épithéliale par l’établissement de contacts cellules-cellules spécifiques entre les cellules épithéliales voisines, et joue un rôle dans les fonctions fondamentales de la polarité épithéliale, la barrière paracellulaire et la morphogenèse cellulaire. PLEKHA7 est une protéine récemment identifié appartenant aux jonctions adhérentes, où elle est présente dans les deux complexes majeures d’adhésions, basé sur les cadherines et les nectines, à travers l’interaction d’avec les composants cytoplasmiques p120ctn et afadine [5-7]. PLEKHA7 fait partie d’un complexe connectant l’E-cadherine aux microtubules du cytosquelette, et stabilise la zonula adhaerens (ZA) [5]. Des études génétiques et génomiques ont montré que PLEKHA7 est impliquée dans la régulation de la signalisation des micro ARNs, dans l’hypertension, dans la régulation de la contractilité cardiaque et dans le glaucome [8-11]. Toutefois, les mécanismes moléculaires à travers lesquels PLEKHA7 participe dans la physiologie et la pathologie des différents tissues restent inconnus. Dans ma thèse, je rapporte de nouveaux résultats qui ont aidé à découvrir les fonctions de PLEKHA7 dans les cellules épithéliales et endothéliales, à travers 4 l’identification d’une nouvelle molécule qui interagit avec PLEKHA7, PDZD11, par le criblage à deux hybrides de levures, des analyses de spectrométrie de masse, de co-immunoprécipiation et de pull-down. J’ai analysé les bases structurelles de leur interaction, montrant que le domaine WW de PLEKHA7 se lie à la région N-terminale de PDZD11; cette interaction est fonctionnellement essentielle, car PLEKHA7 est responsable du recrutement de PDZD11 aux jonctions cellule-cellule. Ainsi, j’ai identifié PDZD11 comme une nouvelle protéine des jonctions adhérentes. Par ailleurs, j’ai fourni des preuves que PDZD11 forme un complexe avec les nectines dans les jonctions adhérentes, et que son domaine PDZ se lie au motif des nectines liant PDZ. PDZD11 stabilise les nectines et régule le début des premières étapes de l’assemblage jonctionnel. En résumé, mon travail a permis de découvrir une nouvelle fonction de PLEKHA7 dans le recrutement de PDZD11 dans les jonctions adhérentes, et a montré que le complexe PLEKHA7-PDZD11 stabilise le complexe des nectines dans les jonctions adhérentes, promouvant l’efficacité des premières étapes dans l’assemblage des jonctions. Ces résultats suggèrent un rôle de PLEKHA7 dans le recrutement et la stabilisation des protéines liant PDZ aux jonctions adhérentes, ouvrant de nouvelles perspectives dans la compréhension des mécanismes moléculaires sous-jacents le rôle de PLEKHA7 dans la physiologie et pathologie cellulaire. 5 ABSTRACT Epithelial cells provide a barrier between the external and internal body environments and define tissue compartmentalization within organs, by covering all body surfaces and lining all internal body cavities. Vertebrate polarized epithelial cells are characterized by a junctional complex, comprising tight junctions (TJ), adherens junctions (AJ) and desmosomes (D). The junctional complex is responsible for epithelial adhesion through the establishment of specific cell-cell contacts between neighboring epithelial cells, and mediates fundamental functions in epithelial polarity, paracellular barrier, and cell morphogenesis. PLEKHA7 is a recently identified protein of the AJ, where it is present at both major adhesive protein complexes, based on cadherin and nectin, respectively, through its interaction with the cytoplasmic components p120ctn and afadin
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