Cholera toxin B-subunit prevents activation and proliferation of human CD4+ T cells by activation of a neutral sphingomyelinase in lipid rafts.
The inhibition of human CD4+ T lymphocyte activation and proliferation by cholera toxin B-subunit (CTB) is a well-established phenomenon; nevertheless, the exact mechanism remained unclear. In the present study, we propose an explanation for the rCTB-induced inhibition of CD4+ T lymphocytes. rCTB specifically binds to GM1, a raft marker, and strongly modifies the lipid composition of rafts. First, rCTB inhibits sphingomyelin synthesis; second, it enhances phosphatidylcholine synthesis; and third, it activates a raft-resident neutral sphingomyelinase resembling to neutral sphingomyelinase type 1, thus generating a transient ceramide production. We demonstrated that these ceramides inhibit protein kinase Calpha phosphorylation and its translocation into the modified lipid rafts. Furthermore, we show that rCTB-induced ceramide production activate NF-kappaB. Combined all together: raft modification in terms of lipids, ceramide production, protein kinase Calpha inhibition, and NF-kappaB activation lead to CD4+ T cell inhibition.
Rouquette-Jazdanian
Alexandre K
AK
Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 576, IFR 50, Hôpital de l'Archet I, Nice Cedex 3, France.
Foussat
Arnaud
A
Lamy
Laurence
L
Pelassy
Claudette
C
Lagadec
Patricia
P
Breittmayer
Jean-Philippe
JP
Aussel
Claude
C
D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002518:Ceramides / Q000096:biosynthesis; D002772:Cholera Toxin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005677:G(M1) Ganglioside / Q000096:biosynthesis / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D021962:Membrane Microdomains / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D021381:Protein Transport; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D013109:Sphingomyelins / Q000378:metabolism
D002518:Ceramides; D016328:NF-kappa B; D013109:Sphingomyelins; D005677:G(M1) Ganglioside; D015759:Ionomycin; D002772:Cholera Toxin; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione; D000111:Acetylcysteine