Nucleosomes Are Exposed at the Cell Surface in Apoptosis

Abstract

Apoptotic cells are considered the source of DNA, histones, and nucleoprotein complexes that drive the production of autoantibodies in systemic lupus erythematosus. However, the role of apoptotic cells in the activation of the immune system is not clear. To explore interactions that may initiate or sustain the production of anti-nuclear autoantibodies, we characterized the binding of a large panel of monoclonal autoantibodies to apoptotic cells. Autoantibodies to DNA, individual core histones, histone-DNA complexes, or the native nucleosome core particle revealed a consistent and specific binding pattern in confocal microscopy. Immunoreactive epitopes were detected in the cytoplasm and accumulated along the surface of the fragmenting nucleus in a caspase-dependent manner. Ag-Ab complexes on nuclear fragments that had emerged from the plasma membrane were accessible to anti-isotype-reactive microparticles. Moreover, autoantibodies specific for the nucleosome core or its molecular components selectively precipitated a complex of core histones and DNA from the cytosol at 4 h after induction of apoptosis. These observations identify distinct steps in the release of nucleosomes from the nucleus and their exposure at the cell surface. Furthermore, the results indicate a direct role for nucleosomes in the execution of apoptosis, clearance of apoptotic cells, and regulation of anti-nuclear autoantibody production.

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

“…9B). Unlike authentic anti-DNA autoantibodies (61), none of the above Abs bound to the surface of nuclear fragments, implying that these Abs do not recognize DNA-histone, subnucleosomal complexes, or intact nucleosomes. …”

“…Specific targets of anti-dsDNA Abs include blebs formed by the protrusion of nuclear fragments from the cell surface. AntidsDNA Abs may also cross-react with phospholipid structures associated with the inner plasma membrane that become externalized during apoptosis (61)(62)(63)(64)(65). As shown in Fig.…”

“…Because 56RV 21D-and 56RV x-expressing hybridomas secreted IgM Abs that bind dsDNA, albeit with low affinity, it was of interest to know whether these Abs would also bind to apoptotic Jurkat cells since anti-dsDNA Abs often bind to apoptotic cells (61). Specific targets of anti-dsDNA Abs include blebs formed by the protrusion of nuclear fragments from the cell surface.…”

Apoptosis in the pathogenesis of systemic lupus erythematosus

“…Nuclear autoantigens (chromatin) targeted in SLE are clustered in blebs at the surface of apoptotic cells. 12 Normally, phagocytes will quickly remove apoptotic cells and blebs long before they could have released their modified contents. In SLE, the processes of apoptosis and/or the clearance of apoptotic material may be disturbed (reviewed in 10 ).…”

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

“…[15][16][17] Konishi et al recently reported new insights into the death signal transmission pathway. 18 They demonstrated the apoptogenic ability of histone H1.2 when this protein translocated from the nucleus into the cytosol after DNA double-strand breaks.…”