Analysis of relationship between autoimmune response and, structure and function of proteasome-PCNA multiprotein complex

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We have previously shown that a group of anti-PCNA monoclonal antibodies (mAbs) raised in our laboratory can react with PCNA bound to or interacting with other proteins associated with cell proliferation (PCNA complexes). In addition, we have found that proteasome is also interacting with PCNA and showed that the proteasome interacting with PCNA is the hybrid-type proteasome consisted of PA700, 20S proteasone and PA28(γ). We then analyzed autoimmune response of proteins in the proretasome in patients with various connective tissue disease, and found that 24% of sera from patients with systemic lupus erythematosus (SLE) and 13% of sera from Sjogren's syndrome (SjS) reacted with PA28γ, whereas 26% of lupus sera and 23% of sera from SjS reacted with PA28α. These results suggested that autoantigens targeted by SLE and SjS are different although both two proteins are the same components of proteasome. We also found that the occurrence of the autoimmune response to these proteins had a significant linkage. To analyze the mechanisms of the linkage, we tested autoimmune response to the components of 20S proteasome that is interacting with both two proteins. Then, we found that the frequency of antibodies to PA28αand PA28γ became three times higher if the sera were reactive with α subunit of 20S proteasome. In addition, a linkage of autoimmune response between PCNA and proteasome was also shown, and the frequency of antibodies to PCNA increased 10 times higher among those sera. Taken together, these findings suggest that "antige presentation" is playing a critical role to induce the autoimmune response to the PCNA complex including proteasome.