Nucleated Cell Death by a Single Hole Generated by C5b-9

Abstract

AbstractCell death is essential for tissue regeneration and removal of pathogenic cells. Immunological cell death is caused by membrane attack complex (MAC) or bacterial perforins. A complete understanding of nucleated cell death or bacterial cell death by MAC is essential for therapeutic interventions. The mechanism of MAC mediated cell death in nucleated cell is controversial. We know show that MAC causes cell death in nucleated cells by creating a large single hole in the membrane. Our results are contrary to the current paradigm that states “MAC kills nucleated cell by multiple hits”. MAC deposition on the cell membrane also trigger clustering of membrane rafts, which will have relevant consequences for enhanced cell signaling.Significance StatementProteins of late complement pathway that form membrane attack complex, cause death of undesirable nucleated cells such as lymphocytes. The structure of these proteins and their similarity to bacterial cytolysins has been studied. How C9 pore forming protein assemble with rest of C5b-8 on nucleated cell membrane remains controversial. We thus examined and now show the structures formed by these proteins on nucleated cell membranes. Formation of MAC occurs during complement activation during infection and autoimmunity. Largely, our current knowledge of the membrane pore formation is gained using ghost cells, lipid micelles, and erythrocytes. Understanding of how MAC kills nucleated cells will enhance our ability to design new therapies for selective killing of pathogens.