title: Involvement of the cytoplasmic cysteine-238 of CD40 in its up-regulation of CD23 expression and its enhancement of TLR4-triggered responses.
abstract: CD40, a member of the tumor necrosis factor receptor superfamily, plays a key role in both adaptive and innate immunity. Engagement of CD40 with its natural trimeric ligand or with cross-linked antibodies results in disulfide-linked CD40 (dl-CD40) homodimer formation, a process mediated by the cysteine-238 residues of the cytoplasmic tail of CD40. The present study was designed to elucidate the biological relevance of cysteine-238-mediated dl-CD40 homodimers to the expression of CD23 on B cells and to investigate its possible involvement in the innate response. Our results indicate that cysteine-238-mediated dl-CD40 homodimerization is required for CD40-induced activation of PI3-kinase/Akt signaling and the subsequent CD23 expression, as inhibition of dl-CD40 homodimer formation through a point mutation-approach specifically impairs these responses. Interestingly, cysteine-238-mediated dl-CD40 homodimers are also shown to play a crucial role in Toll-like receptor 4-induced CD23 expression, further validating the importance of this system in bridging innate and adaptive immune responses. This process also necessitates the activation of the PI3-kinase/Akt cascade. Thus, our results highlight new roles for CD40 and cysteine-238-mediated CD40 homodimers in cell biology and identify a potential new target for therapeutic strategies against CD40-associated chronic inflammatory diseases.
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), 900 rue Saint-Denis, Tour Viger, Montréal, Québec H2X 0A9, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: Nadiri
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), 900 rue Saint-Denis, Tour Viger, Montréal, Québec H2X 0A9, Canada.
authors.forename: Malek
authors.initials: M
authors.lastname: Jundi
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), 900 rue Saint-Denis, Tour Viger, Montréal, Québec H2X 0A9, Canada.
authors.forename: Souhad
authors.initials: S
authors.lastname: El Akoum
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), 900 rue Saint-Denis, Tour Viger, Montréal, Québec H2X 0A9, Canada.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), 900 rue Saint-Denis, Tour Viger, Montréal, Québec H2X 0A9, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yacoub
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), 900 rue Saint-Denis, Tour Viger, Montréal, Québec H2X 0A9, Canada mw.mourad@umontreal.ca.
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017455:Receptors, IgE / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019013:CD40 Antigens; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003545:Cysteine
keywords: CD23; CD40; Toll-like receptor; cell activation; cysteine; dimerization