Open AccessRecruitment of topoisomerase I (Scl‐70) to nucleoplasmic proteasomes in response to xenobiotics suggests a role for altered antigen processing in scleroderma
Author(s) -
Chen Min,
Dittmann Assemgul,
Kuhn Annegret,
Ruzicka Thomas,
Mikecz Anna von
Publication year - 2005
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.20962
Subject(s) - biology , proteasome , autoantibody , immunology , immune system , cell nucleus , antibody , autoimmune disease , autoimmunity , microbiology and biotechnology , cytoplasm
Abstract Objective Scleroderma, also known as systemic sclerosis (SSc), is a chronic, life‐threatening autoimmune disease characterized by a wide spectrum of manifestations and a variable evolution. The presence of particular antinuclear antibodies is often predictive of the clinical expression and prognosis of the disease, but the molecular mechanisms of the immune responses remain unclear. Recently, we have shown xenobiotic‐induced recruitment of nuclear autoantigens to proteasomes in the cell nucleus in cell culture and in animal models in correlation with a unique autoantibody response. In this study, we attempted to validate our findings in patients with SSc. Methods Using indirect immunofluorescence microscopy, run‐on replication and transcription assays, immunoblotting, and proteasome activity assays, we analyzed the nuclear structure, function, and proteasomal proteolysis in HEp‐2 cells treated with xenobiotics or left untreated. Blood dendritic cells (DCs) were isolated from 30 patients with SSc and age‐ and sex‐matched control subjects to determine the subcellular localization of SSc autoantigens in relation to proteasomes. Results Xenobiotics induced a relocation of the SSc autoantigen DNA topoisomerase I (Scl‐70, topo I) to nucleoplasmic clusters, where proteasomes degrade topo I. Colocalization of topo I with proteasomes occurred exclusively in DCs from patients with SSc who developed antibodies against this autoantigen. Neither centromeres nor other SSc autoantigens colocalized with proteasomes in DCs from patients with SSc or from control subjects. Conclusion Alteration of nuclear structure and function by xenobiotics induces recruitment of the nuclear autoantigen topo I for proteasomal processing. This event may, in turn, lead to subsequent presentation of the resulting peptides on the cell surface and the autoimmune responses against topo I in SSc.