Viral FLIP blocks Caspase-8 driven apoptosis in the gut in vivo

Abstract

A strict cell death control in the intestinal epithelium is indispensable to maintain barrier integrity and homeostasis. In order to achieve a balance between cell proliferation and cell death, a tight regulation of Caspase-8, which is a key player in controlling apoptosis, is required. Caspase-8 activity is regulated by cellular FLIP proteins. These proteins are expressed in different isoforms (cFLIP long and cFLIP short ) which determine cell death and survival. Interestingly, several viruses encode FLIP proteins, homologous to cFLIP short , which are described to regulate Caspase-8 and the host cell death machinery. In the current study a mouse model was generated to show the impact of viral FLIP (vFLIP) from Kaposi's Sarcoma-associated Herpesvirus (KSHV)/ Human Herpesvirus-8 (HHV-8) on cell death regulation in the gut. Our results demonstrate that expression of vFlip in intestinal epithelial cells suppressed cFlip expression, but protected mice from lethality, tissue damage and excessive apoptotic cell death induced by genetic cFlip deletion. Finally, our model shows that vFlip expression decreases cFlip mediated Caspase-8 activation in intestinal epithelial cells. In conclusion, our data suggests that viral FLIP neutralizes and compensates for cellular FLIP, efficiently counteracting host cell death induction and facilitating further propagation in the host organism.

Interaction between the Hepatitis B Virus and Cellular FLIP Variants in Viral Replication and the Innate Immune System

“…v-FLIP is able to block extrinsic apoptosis through binding to procaspase-8 and interfering with its maturation and activation, proving that v-FLIP acts as a viral inhibitor of caspase-8 [19,21]. However, an interesting report showed that HHV-8-encoding v-FLIP reduced the expression of c-FLIP but alleviated apoptosis induced by loss of c-FLIP in intestinal epithelial cells (IECs) in a mouse model [145]. HHV-8-derived v-FLIP has also been reported to potentiate NF-κB signaling by direct interaction with the IKK complex [146,147].…”

Bcl-xL is required to protect endothelial cells latently infected with KSHV from virus induced intrinsic apoptosis

“…During latent infection, vFLIP is known to block extrinsic apoptosis, programmed cell death mediated by death receptors on the cell membrane. The vFLIP protein induces NF-kB expression to inhibit apoptosis and also contains a domain capable of blocking apoptosis induced by extracellular death inducing factors [ 16 – 18 ]. It was recently shown that Mcl1, an inhibitor of intrinsic apoptosis is required for the survival of PEL cell lines [ 19 ].…”

Viral-mediated activation and inhibition of programmed cell death

“…Additionally, members of KSHV encode cellular FLIP analogs, termed viral FLIPs (vFLIPs). vFLIPs resemble the short isoform of cellular FLIPs and again completely block caspase-8 proteolytic activity [ 153 , 154 ]. Moreover, large DNA viruses infecting arthropods encode viral inhibitors of apoptosis proteins (vIAPs) containing a baculoviruses IAP repeat (BIR) motifs that binds and inhibit apoptosis mediators Hid, Reaper, or Grim.…”