The 52 000 MW Ro/SS-A (Ro52) protein is a major target of autoantibodies in autoimmune conditions such as systemic lupus erythematosus and Sjögren's syndrome. Recent genomic and bioinformatic studies have shown that Ro52 belongs to a large family of related RING/Bbox/coiled-coil (RBCC) tripartite motif proteins sharing overall domain structure and 40-50% identity at the amino acid level. Ro52 also has a B30.2 domain at the C-terminus. Using the human genome draft sequence, the genomic organization of the Ro52 gene on human chromosome 11p15.5 has been deduced and related to the protein domain structure. We show that the steady-state levels of Ro52 mRNA are normally very low but are induced by cell activation with interferon-gamma. In transient transfection of HeLa cells, epitope-tagged Ro52 protein was localized to unidentified membrane proximal rod-like structures. Using in vitro coupled transcription/translation followed by immunoprecipitation, the autoimmune response to Ro52 protein was investigated and two distinct interactions were resolved. The Ro52 C-terminal B30.2 domain interacts with human immunoglobulin independently of antibody specificities. Sera derived from patients with Sjögren's syndrome and systemic lupus erythematosus, in addition, contained specific autoantibodies directed towards the rest of the Ro52 molecule. The majority of these autoimmune sera also immunoprecipitated the Ro52-related molecule RNF15. A possible role for Ro52 protein in alterations of plasma membranes during cellular activation or apoptosis is discussed.