Catalyzes calcium-induced ATP-independent rapid bidirectional and non-specific movement of phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer leaflet of the plasma membrane resulting in collapse of the phospholipid asymmetry which leads to phosphatidylserine externalization on the cell surface (PubMed:9218461, PubMed:8663431, PubMed:10770950, PubMed:9572851, PubMed:9485382, PubMed:18629440, PubMed:23590222, PubMed:24648509, PubMed:24343571, PubMed:32110987, PubMed:23659204, PubMed:29748552). Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with TRPC5 (By similarity). Also exhibits magnesium-dependent nuclease activity against double-stranded DNA and RNA but not single-stranded DNA and can enhance DNA decatenation mediated by TOP2A (PubMed:27206388, PubMed:17567603). Negatively regulates FcR-mediated phagocytosis in differentiated macrophages (PubMed:26745724). May contribute to cytokine-regulated cell proliferation and differentiation (By similarity). May play a role in the antiviral response of interferon (IFN) by amplifying and enhancing the IFN response through increased expression of select subset of potent antiviral genes (PubMed:15308695). Inhibits the functions of viral transactivators, including human T-cell leukemia virus (HTLV)-1 protein Tax, human immunodeficiency virus (HIV)-1 Tat, human hepatitis B virus (HBV) HBx, Epstein-Barr virus (EBV) BZLF1 and human cytomegalovirus IE1 and IE2 proteins through direct interactions (PubMed:22789739, PubMed:31434743, PubMed:25365352, PubMed:23501106, PubMed:35138119). Mediates also the inhibition of influenza virus infection by preventing nuclear import of the viral nucleoprotein/NP (PubMed:29352288, PubMed:35595813). Plays a crucial role as a defense factor against SARS-CoV-2 independently of its scramblase activity by directly targeting nascent viral vesicles to prevent virus-membrane fusion and the release of viral RNA into the host-cell cytosol (PubMed:37438530).

(Microbial infection) Acts as an attachment receptor for HCV.