Human-Gyrovirus-Apoptin Triggers Mitochondrial Death Pathway—Nur77 is Required for Apoptosis Triggering

Abstract

The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin–induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin–induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin–induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway.

Human viruses have codon usage biases that match highly expressed proteins in the tissues they infect

“…Human gyrovirus 1, which is identical to the Chicken Anemia Virus, is relatively rare and the effects of the virus still remain largely unknown, although it may affect the apoptosis pathway [28,29].…”

Hepatitis B and C virus-induced hepatitis: Apoptosis, autophagy, and unfolded protein response

“…Previous reports have shown that caspase-3 cleavage is one of the most important hallmarks of apoptosis activation in different models [6,32,33] . The results of immunofluorescence staining showed that both HBV and HCV infection induce caspase-3 cleavage in infected hepatocytes ( Figure 4A…”

Human Gyrovirus-Apoptin Interferes with the Cell Cycle and Induces G2/M Arrest Prior to Apoptosis

“…A homolog of chicken anemia virus Apoptin (CAVApoptin), human gyrovirus-Apoptin (HGyv-Apoptin) also induces apoptosis selectively in cancer cells and functions independently from p53 (Chaabane et al 2014;Rollano Penaloza et al 2014). Little is known about the molecular mechanism of action of HGyv-Apoptin.…”