LEDGF/p75: a novel nuclear autoantigen at the crossroads of cell survival and apoptosis

Abstract

Intracellular autoantigens recognized by autoantibodies in systemic autoimmune and other chronic inflammatory disorders often undergo proteolytic cleavage during apoptosis. Cleaved autoantigens may display altered functions and higher immunogenicity, and could potentially elicit autoantibody responses under a pro-inflammatory environment. LEDGF/p75 (lens epithelium derived growth factor p75) is a ubiquitous nuclear autoantigen targeted by autoantibodies in subsets of patients with atopic disorders, mainly atopic dermatitis, and other inflammatory conditions involving dysregulated apoptosis. Anti-LEDGF/p75 autoantibodies have been shown to have cytotoxic activity, suggesting their involvement in pathogenesis. LEDGF/p75 confers cellular protection against stress-induced apoptosis via transcriptional activation of stress-related genes. Recent studies in our laboratory established that LEDGF/p75 belongs to a selected group of autoantigens that are targeted for cleavage during cell death. In apoptotic cells, caspases cleave this protein at three sites located within functionally important domains, generating two fragments of 65 and 58 kD. Caspase cleavage not only abolishes the survival function of LEDGF/p75 but may generate variants of the protein that enhance apoptosis. A model is proposed in which caspase-induced LEDGF/p75 cleavage and the generation of autoantibodies to the protein might contribute to the pathogenesis of various human atopic and inflammatory disorders associated with dysregulated apoptosis.