title: Viral FLICE inhibitory protein of rhesus monkey rhadinovirus inhibits apoptosis by enhancing autophagosome formation.
abstract: Rhesus monkey rhadinovirus (RRV) is a gamma-2 herpesvirus closely related to human herpesvirus 8 (HHV8). RRV encodes viral FLICE inhibitory protein (vFLIP), which has death effector domains. Little is known about RRV vFLIP. This study intended to examine its function in apoptosis. Here we found that RRV vFLIP inhibits apoptosis induced by tumor necrosis factor-α (TNF-α) and cycloheximide. In HeLa cells with vFLIP expression, the cleavage of poly [ADP-ribose] polymerase 1 (PARP-1) and activities of caspase 3, 7, and 9 were much lower than those in controls. Cell viability of HeLa cells with vFLIP expression was significantly higher than control cells after apoptosis induction. However, RRV vFLIP appears unable to induce NF-κB signaling when tested in NF-κB reporter assay. RRV vFLIP was able to enhance cell survival under starved conditions or apoptosis induction. At early time points after apoptosis induction, autophagosome formation was enhanced and LC3-II level was elevated in cells with vFLIP and, when autophagy was blocked with chemical inhibitors, these cells underwent apoptosis. Moreover, RRV latent infection of BJAB B-lymphoblastoid cells protects the cells against apoptosis by enhancing autophagy to maintain cell survival. Knockdown of vFLIP expression in the RRV-infected BJAB cells with siRNA abolished the protection against apoptosis. These results indicate that vFLIP protects cells against apoptosis by enhancing autophagosome formation to extend cell survival. The finding of vFLIP's inhibition of apoptosis via the autophagy pathway provides insights of vFLIP in RRV pathogenesis.
authors: Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, United States of America.
authors: Krit
authors: K
authors: Ritthipichai
authors: Yuchen
authors: Y
authors: Nan
authors: Ioannis
authors: I
authors: Bossis
authors: Yanjin
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008253:Macaca mulatta; D010588:Phagosomes / Q000187:drug effects*; D018144:Rhadinovirus / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide