CHARACTERIZATION OF NOVEL SUBSTRATE OF THE COMPLEMENT SERINE PROTEASE C1S

Abstract

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A POLYGENIC AUTOIMMUNE DISEASE. HOWEVER, HOMOZYGOUS DEFICIENCY OF EARLY CLASSICAL PATHWAY COMPONENTS (C1Q, C1R, C1S, OR C4) EXHIBITS CAUSAL ASSOCIATION WITH SLE PATHOGENESIS WITH UNCLEAR MECHANISMS. IN THIS STUDY, WE HYPOTHESIZE THAT C1R AND C1S, TWO COMPLEMENT SERINE PROTEASES KNOWN FOR THEIR SPECIFICITIES FOR C2 AND C4, MAY BE RECRUITED TO APOPTOTIC CELLS THROUGH C1Q AND DEGRADE EXPOSED INTRACELLULAR AUTOANTIGENS, SO AS TO PREVENT AUTOREACTIVE B CELL ACTIVATION. WE OBSERVED THAT C1Q BOUND UV-IRRADIATED APOPTOTIC CELLS PROGRESSIVELY FROM THE PERIPHERY TO THE NUCLEOLUS. IN GRADIENT CENTRIFUGATION, C1Q CO-SEDIMENTED WITH NUCLEOLUS. INCUBATION OF C1 COMPLEX WITH ISOLATED NUCLEOLUS CAUSED DEGRADATION OF NUCLEOLAR ANTIGENS SUCH AS B23 AND NUCLEOLIN, AND THIS WAS INHIBITED BY C1 INHIBITOR. POTENTIAL CLEAVAGE SITES ON B23 WERE EVALUATED THROUGH MUTAGENESIS. THESE RESULTS HELP TO EXPLAIN WHY C1R/C1S DEFICIENCY CAUSES SLE.