title: Increased Goodpasture antigen-binding protein expression induces type IV collagen disorganization and deposit of immunoglobulin A in glomerular basement membrane.
abstract: Increased expression of Goodpasture antigen-binding protein (GPBP), a protein that binds and phosphorylates basement membrane collagen, has been associated with immune complex-mediated pathogenesis. However, recent reports have questioned this biological function and proposed that GPBP serves as a cytosolic ceramide transporter (CERT(L)). Thus, the role of GPBP in vivo remains unknown. New Zealand White (NZW) mice are considered healthy animals although they convey a genetic predisposition for immune complex-mediated glomerulonephritis. Here we show that NZW mice developed age-dependent lupus-prone autoimmune response and immune complex-mediated glomerulonephritis characterized by elevated GPBP, glomerular basement membrane (GBM) collagen disorganization and expansion, and deposits of IgA on disrupted GBM. Transgenic overexpression of human GPBP (hGPBP) in non-lupus-prone mice triggered similar glomerular abnormalities including deposits of IgA on a capillary GBM that underwent dissociation, in the absence of an evident autoimmune response. We provide in vivo evidence that GPBP regulates GBM collagen organization and its elevated expression causes dissociation and subsequent accumulation of IgA on the GBM. Finally, we describe a previously unrecognized pathogenic mechanism that may be relevant in human primary immune complex-mediated glomerulonephritis.
authors.affiliation: Centro de Investigación Príncipe Felipe, Valencia, Spain. jsaus@cipf.es
authors.forename: Fernando
authors.initials: F
authors.lastname: Revert
authors.forename: Ramón
authors.initials: R
authors.lastname: Merino
authors.forename: Carlos
authors.initials: C
authors.lastname: Monteagudo
authors.forename: Jesús
authors.initials: J
authors.lastname: Macias
authors.forename: Amando
authors.initials: A
authors.lastname: Peydró
authors.forename: Javier
authors.initials: J
authors.lastname: Alcácer
authors.forename: Pedro
authors.initials: P
authors.lastname: Muniesa
authors.forename: Regina
authors.initials: R
authors.lastname: Marquina
authors.forename: Mario
authors.initials: M
authors.lastname: Blanco
authors.forename: Marcos
authors.initials: M
authors.lastname: Iglesias
authors.forename: Francisco
authors.initials: F
authors.lastname: Revert-Ros
authors.forename: Jesús
authors.initials: J
authors.lastname: Merino
authors.forename: Juan
authors.initials: J
authors.lastname: Saus
mesh_terms: D000375:Aging / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D024141:Collagen Type IV / Q000276:immunology / Q000378:metabolism*; D050533:Glomerular Basement Membrane / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D013045:Species Specificity
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D024141:Collagen Type IV; D007070:Immunoglobulin A; C119090:CERT1 protein, human; D017346:Protein Serine-Threonine Kinases