A NOVEL PROTEIN THAT PARTICIPATES IN NONSELF DISCRIMINATION OF MALIGNANT-CELLS BY HOMOLOGOUS COMPLEMENT

The human complement (C) system protects an individual against substan ces of nonself origin, including xenografts and microbial pathogens'. Human cells express C-regulatory proteins, CD46 and CD55, thereby circ umventing attack by C3, a major effector of C (ref. 2). Nevertheless, certain malignant cells, particularly those undergoing apoptotic stres s, can activate homologous C, overcoming the regulatory actions of CD4 6 and/or CD55 (ref. 3-5). The molecular mechanisms whereby malignant c ells are tagged by homologous C3 remain largely unknown. We identified a novel gene product that converts human cells into targets for homol ogous complement. Only malignant cells and cell lines exposed to Fas o r X-irradiation stimuli produced this protein, designated M161Ag, whic h was an unglycosylated 43-kDa protein. Analysis of cloned cDNAs indic ated that this molecule was a secretory protein containing five amino acids encoded by TGA codons. Its functions were unique in that once se creted from the tumor cells, it bound back to the surface of these cel ls and activated homologous complement (C3) via the alternative pathwa y, allowing for C3 deposition on the membrane. This molecule may offer new insight into innate immunity; surveillance of tumor cells by comp lement is a common feature in the human immune system.