Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors

Abstract

Viruses have evolved many distinct strategies to avoid the host's apoptotic response. Here we describe a new family of viral inhibitors (v-FLIPs) which interfere with apoptosis signalled through death receptors and which are present in several gamma-herpesviruses (including Kaposi's-sarcoma-associated human herpesvirus-8), as well as in the tumorigenic human molluscipoxvirus. v-FLIPs contain two death-effector domains which interact with the adaptor protein FADD, and this inhibits the recruitment and activation of the protease FLICE by the CD95 death receptor. Cells expressing v-FLIPs are protected against apoptosis induced by CD95 or by the related death receptors TRAMP and TRAIL-R. The herpesvirus saimiri FLIP is detected late during the lytic viral replication cycle, at a time when host cells are partially protected from CD95-ligand-mediated apoptosis. Protection of virus-infected cells against death-receptor-induced apoptosis may lead to higher virus production and contribute to the persistence and oncogenicity of several FLIP-encoding viruses.

Modulation of life and death by the TNF receptor superfamily

“…Since these proteins contain a death e ector domain, it is possible that they perform functions analogous to those of FADD (Thome et al, 1997;Shu et al, 1997;Hu et al, 1997).…”

Type I interferons are essential mediators of apoptotic death in virally infected cells

“…For example, the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) upregulates the expression of bcl-2 (Henderson et al 1991;Korsmeyer 1995), and EBV itself encodes BHRF1, a protein homologous to Bcl-2 which shows anti-apoptotic activity (Henderson et al 1993). In addition, g-herpesviruses, including Kaposi's sarcoma associated human herpesvirus-8, encode v-FLIPs (viral FLICE-inhibitory proteins) which inhibit the activation of the protease FLICE induced by CD95 (Fas/Apo-1) or by related cell death-inducting receptors (Thome et al 1997). Furthermore, viral oncoproteins, such as simian virus 40 T antigen, human papilloma virus E6 and adenovirus E1B inactivate p53, thereby suppressing the p53-dependent pathway of apoptosis (Levine et al 1991;Vogelstein & Kinzler 1992;Shen & Shenk 1995).…”

Increased spontaneous, tumor necrosis factor receptor- and CD95 (Fas)-mediated apoptosis in cord blood T-cell subsets from Turner's syndrome

“…22,23 FLIP inhibits apoptosis via interaction with DED of FADD and thereby inhibits recruitment of procaspase-8 to the DISC, and activation of procaspase-8 to active caspase-8. In addition, FLIP provides a survival signal by activating ERK and NFkB.…”