Generation and characterization of ecto-ADP-ribosyltransferase ART2.1/ART2.2-deficient mice.
This is the first study reporting the inactivation of a member of the mouse gene family of toxin-related ecto-ADP-ribosyltransferases (ARTs). Transfer of the ADP-ribose moiety from NAD onto extracellular arginine residues on T-cell membrane proteins is mediated by glycosylphosphatidylinositol-linked cell surface ARTs. Exposure of T cells to ecto-NAD blocks T-cell activation and induces T-cell apoptosis. To determine a possible role of ecto-ART2.1 and ART2.2 in these processes, we generated ART2.1/ART2.2 double-knockout mice. ART2-deficient mice were healthy and fertile and showed normal development of lymphoid organs. ART2-deficient T cells showed a dramatically reduced capacity to ADP-ribosylate cell surface proteins, indicating that most if not all ART activity on the T-cell surface can be attributed to the ART2s. Moreover, ART2-deficient T cells were completely resistant to NAD-induced apoptosis and partially resistant to NAD-mediated suppression of proliferation. These results demonstrate that the ART2 ectoenzymes are an essential component in the regulation of T-cell functions by extracellular NAD, e.g., following release of NAD upon lysis of cells in tissue injury and inflammation.
Ohlrogge
Wiebke
W
Institute of Immunology. Heinrich Pette Institute, University Hospital, Hamburg 20246, Germany.
Haag
Friedrich
F
Löhler
Jürgen
J
Seman
Michel
M
Littman
Dan R
DR
Killeen
Nigel
N
Koch-Nolte
Friedrich
F
D036002:ADP Ribose Transferases / Q000737:chemistry* / Q000235:genetics*; D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005822:Genetic Vectors; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology; D015854:Up-Regulation; D000099192:CD69 Antigens
D036002:ADP Ribose Transferases; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens; C449322:Art2a protein, mouse; C449339:Art2b protein, mouse