Abstract:
Apoptosis-inducing factor (AIF) is a flavoprotein that, upon translocation to the nucleus, induces DNA fragmentation, leading to apoptosis via a caspase-independent pathway. This study demonstrates that the E6 component of human papillomavirus (HPV) inhibits this activity. E6 is able to bind to all of three forms of AIF (precursor, mature, and apoptogenic) and co-localized with apoptogenic AIF. E6 derived from HPV16 (a known cancer-causing type) lead to the degradation of AIF. This degradation was blocked by the proteasome inhibitor MG132. Of interest, degradation of AIF was not induced by E6 derived from HPV6 (a type that does not cause cancer). E6 from HPV16, but not E6 from HPV6, suppressed AIF-induced chromatin degradation in vitro and STS (a protein kinase inhibitor)-induced apoptosis in vivo. Moreover, there was a significant decrease in apoptosis in HPV6 E6-expressing cells when treated with AIF siRNA, but not in HPV16 E6-expressing cells after STS treatment. These findings demonstrate that E6 from cancer-inducing HPV types block AIF-mediated apoptosis and that AIF may represent a novel therapeutic target for HPV-induced cervical cancer.
