Cell-penetrating autoantibody induces caspase-mediated apoptosis through catalytic hydrolysis of DNA

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

“…1C). This is quite a surprising observation because cell-penetrating anti-DNA Abs reported so far eventually accumulated in the nucleus, usually within a few hours of internalization [3,10,11,14,26]. The majority of CPPs, such as Tat and arginine-rich peptides, also preferentially localize in the nucleus [2].…”

“…7D) demonstrated that 3D8 scFv induced apoptotic cell death. Previous reports have shown that cell-penetrating anti-DNA Abs with DNA-hydrolyzing activity also showed cytotoxicity, triggering apoptosis in various cancer cells [3,6]: anti-DNA Abs were internalized and accumulated in the nucleus, leading the authors to postulate that apoptotic cell death was triggered by damage to nuclear DNA [3,6]. Unlike the above cellpenetrating anti-DNA Abs, however, the final destination of 3D8 scFv up to 48 h was the cytosol without accumulation in the nucleus (Fig.…”

“…Unlike CPPs which do not generally exhibit cytotoxicity, cellpenetrating anti-DNA Abs with DNA-hydrolyzing activity induced apoptotic cell death [3,4]. Even though their cell-penetrating capacity has not yet been investigated in detail, some polyclonal anti-DNA Abs have shown that their DNA-hydrolyzing activity is correlated with cytotoxicity to tumor cells [5,6].…”

Pathogenic effect of a cell-penetrating anti-dsDNA autoantibody through p38 signaling pathway and pro-inflammatory cytokine stimulation in mesangial cells

“…There is accumulating evidence for the pathogenic role of antidsDNA autoAbs in induction and progress of the diseases (Jang et al 1996;Putterman 2004;Isenberg et al 2007;Im et al 2015). It has been reported by different research groups including ourselves that some autoAbs have cell-penetrating properties, and this subset of Abs could be involved in pathogenesis (Alarcon-Segovia et al 1978;Lee et al 2007;Jang et al 2009;Im et al 2015). However, the mechanism(s) by which cell-penetrating autoAbs contribute to the diseases are not well understood.…”

“…The recombinant 2C10 VH single domain has been produced by engineering the structure of 2C10 IgG (Im et al 2015(Im et al , 2017. The penetrating autoAbs can amplify disease severity by affecting the target cells in various ways (Kubota et al 1996;Sun et al 2000;Yu et al 2001;Lee et al 2007;Jang et al 2009;Im et al 2015). Cytokines released by MES cells could lead to stimulation of other pro-inflammatory cytokines and inflammation of renal tissues, resulting in kidney damage (Graninger et al 2000;Feng et al 2012).…”