Apoptotic nucleolus is recognized by complement C1q and degraded by C1 proteases

Abstract In infections, complement C1q recognizes pathogen-congregated antibodies and elicits complement activation. Among endogenous ligands, C1q binds to DNA and apoptotic cells but whether C1q binds to nuclear DNA in apoptotic cells remains to be investigated. With UV-induced apoptosis, C1q initially bound to peripheral cellular regions in early apoptotic cells. By 6 hr, binding concentrated in the nuclei to the nucleolus but not the chromatins. When nucleoli were isolated from non-apoptotic cells, C1q also bound to these structures. By affinity chromatography, a number of nuclear proteins were found to bind to C1q including nucleophosmin 1 and nucleolin. In vivo, C1q exists as C1 complex (C1qC1r2C1s2) and C1q binding to ligands activates the C1r/C1s proteases. Incubation of nucleoli with C1 caused degradation of nucleolar proteins neucleolin and nucleophosmin 1. Cleavage of purified nucleophosin 1 by C1 is studied in details revealing three defined fragments of 11, 17 and 18 kDa, respectively. This was inhibited by C1 inhibitor. The nucleoli are abundant with autoantigens. C1q binding and C1r/C1s degradation of nucleolar antigens during cell apoptosis potentially reduce autoimmunity. These findings suggest broader substrate spectrum of C1 proteases and help understand why genetic C1q and C1r/C1s deficiencies cause systemic lupus erythematosus.