title: Opa proteins of pathogenic neisseriae initiate Src kinase-dependent or lipid raft-mediated uptake via distinct human carcinoembryonic antigen-related cell adhesion molecule isoforms.
abstract: Several pathogenic bacteria exploit human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for adhesion to and invasion into their host cells. CEACAM isoforms have characteristic expression patterns on epithelial, endothelial, or hematopoietic cells, providing bacteria with distinct sets of receptors on particular tissues. For example, while CEACAM1 and CEACAM6 have a wide tissue distribution, CEACAM3, CEACAM4, and CEACAM8 are uniquely expressed on primary human granulocytes, whereas CEA and CEACAM7 are limited to epithelia. By reconstitution of a CEACAM-deficient cell line with individual CEACAMs, we have analyzed the requirements for CEACAM-mediated internalization of Neisseria gonorrhoeae. Our results point to two mechanistically different uptake pathways triggered by either epithelial CEACAMs (CEACAM1, CEA, and CEACAM6) or the granulocyte-specific CEACAM3. In particular, CEACAM3-mediated uptake critically depends on Src family protein tyrosine kinase (PTK) activity, and CEACAM3 associates with the SH2 domains of several Src PTKs. In contrast, epithelial CEACAMs require the integrity of cholesterol-rich membrane microdomains and are affected by cholesterol depletion, whereas CEACAM3-mediated uptake by transfected cells or the opsonin-independent phagocytosis by human granulocytes is not altered in the presence of cholesterol chelators. These results allow the subdivision of all human CEACAMs known to be utilized as pathogen receptors into functional groups and point to important consequences for bacterial engagement of distinct CEACAM isoforms.
authors.affiliation: Lehrstuhl für Zellbiologie, Universität Konstanz, Postfach X908, 78457 Konstanz, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Schmitter
authors.forename: Stefan
authors.initials: S
authors.lastname: Pils
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weibel
authors.forename: Franziska
authors.initials: F
authors.lastname: Agerer
authors.forename: Lisa
authors.initials: L
authors.lastname: Peterson
authors.forename: Alexander
authors.initials: A
authors.lastname: Buntru
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kopp
authors.forename: Christof R
authors.initials: CR
authors.lastname: Hauck
mesh_terms: D001422:Bacterial Adhesion / Q000502:physiology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015169:Colony Count, Microbial; D003600:Cytosol / Q000382:microbiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009344:Neisseria gonorrhoeae / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D015815:Cell Adhesion Molecules; D020033:Protein Isoforms; C090348:Opa protein, Neisseria; D019061:src-Family Kinases