title: Extracellular IgC2 constant domains of CEACAMs mediate PI3K sensitivity during uptake of pathogens.
abstract: BACKGROUND
  Several pathogenic bacteria utilize receptors of the CEACAM family to attach to human cells. Binding to different members of this receptor family can result in uptake of the bacteria. Uptake of Neisseria gonorrhoeae, a gram-negative human pathogen, via CEACAMs found on epithelial cells, such as CEACAM1, CEA or CEACAM6, differs mechanistically from phagocytosis mediated by CEACAM3, a CEACAM family member expressed selectively by human granulocytes.
  
  
  RESULTS
  We find that CEACAM1- as well as CEACAM3-mediated bacterial internalization are accompanied by a rapid increase in phosphatidylinositol-3,4,5 phosphate (PI(3,4,5)P) at the site of bacterial entry. However, pharmacological inhibition of phosphatidylinositol-3' kinase (PI3K) selectively affects CEACAM1-mediated uptake of Neisseria gonorrhoeae. Accordingly, overexpression of the PI(3,4,5)P phosphatase SHIP diminishes and expression of a constitutive active PI3K increases CEACAM1-mediated internalization of gonococci, without influencing uptake by CEACAM3. Furthermore, bacterial uptake by GPI-linked members of the CEACAM family (CEA and CEACAM6) and CEACAM1-mediated internalization of N. meningitidis by endothelial cells require PI3K activity. Sensitivity of CEACAM1-mediated uptake toward PI3K inhibition is independent of receptor localization in cholesterol-rich membrane microdomains and does not require the cytoplasmic or the transmembrane domain of CEACAM1. However, PI3K inhibitor sensitivity requires the Ig(C2)-like domains of CEACAM1, which are also present in CEA and CEACAM6, but which are absent from CEACAM3. Accordingly, overexpression of CEACAM1 Ig(C2) domains blocks CEACAM1-mediated internalization.
  
  
  CONCLUSIONS
  Our results provide novel mechanistic insight into CEACAM1-mediated endocytosis and suggest that epithelial CEACAMs associate in cis with other membrane receptor(s) via their extracellular domains to trigger bacterial uptake in a PI3K-dependent manner.
authors: Lehrstuhl Zellbiologie, Universität Konstanz, Konstanz, Germany.
authors: Maike
authors: M
authors: Voges
authors: Verena
authors: V
authors: Bachmann
authors: Jan
authors: J
authors: Naujoks
authors: Kathrin
authors: K
authors: Kopp
authors: Christof R
authors: CR
authors: Hauck
mesh_terms: D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D001422:Bacterial Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D042783:Endothelial Cells / Q000382:microbiology / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000737:chemistry*; D000072181:Inositol Polyphosphate 5-Phosphatases; D021962:Membrane Microdomains / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009344:Neisseria gonorrhoeae / Q000378:metabolism*; D009345:Neisseria meningitidis / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D007127:Immunoglobulin Constant Regions; D000072181:Inositol Polyphosphate 5-Phosphatases; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D011994:Recombinant Proteins; C069847:CD66 antigens; C060974:phosphatidylinositol 3,4,5-triphosphate