title: HSP90alpha and HSP90beta isoforms selectively modulate MHC class II antigen presentation in B cells.
abstract: Two isoforms of heat shock protein (HSP) 90, alpha and beta, are abundantly expressed in the cytoplasm of cells, yet only HSP90alpha serves as a chaperone to potentiate epitope presentation in the context of MHC class I molecules. By contrast, the role of HSP90 isoforms in MHC class II presentation of exogenous and endogenous Ags remains less clear. Studies here using human B lymphoblasts demonstrate the importance of HSP90alpha and HSP90beta isoforms in selectively regulating class II presentation of the diabetes autoantigen glutamic acid decarboxylase (GAD). Inactivation of HSP90 function using geldanamycin or radicicol inhibited MHC class II presentation of exogenous and endogenous GAD, but did not perturb the presentation of several other intra- and extracellular Ags. Treatment of human B cells with geldanamycin and radicicol did not alter cellular MHC class II expression, but did induce a stress response in these APCs. Yet, cell stress alone failed to perturb MHC class II presentation of GAD. HSP90 was found to associate with select Ags such as GAD in cells and ex vivo. Knockdown of HSP90alpha or HSP90beta expression using small interfering RNA decreased the abundance of each isoform, respectively, but did not affect MHC class II expression or induce a stress response. Notably, disruption of HSP90alpha or HSP90beta expression specifically inhibited class II presentation of the exogenous and endogenous GAD Ag. Precomplexing HSP90 with GAD Ag enhanced exogenous GAD Ag presentation. These results demonstrate a requirement for HSP90alpha and HSP90beta in regulating class II presentation of select Ags.
authors.affiliation: Department of Microbiology and Immunology, Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Josetta L
authors.initials: JL
authors.lastname: Houlihan
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Metzler
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D000949:Histocompatibility Antigens Class II; D047029:Lactams, Macrocyclic; D018942:Macrolides; D020033:Protein Isoforms; C035359:monorden; C001277:geldanamycin