Goodpasture antigen-binding protein, the kinase that phosphorylates the goodpasture antigen, is an alternatively spliced variant implicated in autoimmune pathogenesis

The non-collagenous C-terminal domain of the ag chain of collagen IV is the autoantigen in Goodpasture disease, an autoimmune disorder described only in humans. Specific N-terminal phosphorylation is a biological feature unique to the human domain when compared with other homologous domains lacking immunopathogenic potential. We have recently cloned from a HeLa-derived cDNA library a novel serine/threonine kinase (Goodpasture antigen-binding protein (GPBP)) that phosphorylates the N-terminal region of the human domain (Raya, A. Revert, F, Navarro, S. and Saus J, (1999) J. Biol. Chem. 274, 12642-12649). We show here that the pre-mRNA of GPBP is alternatively spliced in human tissues and that the most common transcript found encodes GPBP Delta 26, a molecular isoform devoid of a 26-residue serine-rich motif, Recombinantly expressed GPBP Delta 26 exhibits lower activity than GPBP, due at least in part to a reduced ability of GPBP Delta 26 to interact and to form very active high molecular weight aggregates. In human tissues, GPBP shows a more limited expression than GPBP Delta 26 but displays a remarkable preference for the small vessels and for histological structures targeted by natural autoimmune responses including alveolar and glomerular basement membranes, the two main targets in Goodpasture disease. GPBP expression is, in turn, up-regulated in the striated muscle of a Goodpasture patient and in other autoimmune conditions including cutaneous lupus erythematosus, pemphigoid, and lichen planus.