Human herpesvirus 8 viral FLICE-inhibitory protein inhibits Fas-mediated apoptosis through binding and prevention of procaspase-8 maturation

J Hum Virol. Mar-Apr 2001;4(2):62-73.

Abstract

Viral FLICE-inhibitory proteins (v-FLIPs) encoded by several herpesviruses and poxviruses share the ability to inhibit apoptosis after engagement of death receptors. In the current article, we provide insights into the mechanisms by which the v-FLIP of human herpesvirus 8 (HHV-8) (also referred to as Kaposi's sarcoma-associated virus) protects cells from apoptosis after Fas-induced signaling. Using v-FLIP expression vectors, our results clearly show that HHV-8 v-FLIP reduces the cleavage of procaspase-8 into its active p18 and p10 protease subunits upon Fas-induced cell death. These results were confirmed by lower caspase-8 and caspase-3 protease activities in extracts of HeLa cells expressing HHV-8 v-FLIP. Coimmunoprecipitation studies further indicate that HHV-8 v-FLIP physically interacts with procaspase-8, but not with Fas-associated protein with death domain in the cellular cytoplasm. These results suggest that binding of HHV-8 v-FLIP to procaspase-8 affects the recruitment and the activation of the latter at the death-induced signaling complex, resulting in diminished apoptotic cascade initiation. Because cellular FLIP was recently reported to modulate promoter containing NF-kappaB motifs and that both HHV-8 and human immunodeficiency virus type 1 (HWV-1) can infect monocytes, we studied the effects of v-FLIP on HIV-1 gene expression. Cotransfection experiments indicated that v-FLIP expression is associated with activation of HIV long terminal repeats: events that were strictly dependent on the presence of NF-kappaB consensus elements. In conclusion, HHV-8 v-FLIP can possibly contribute to the pathogenesis of both HHV-8 and HIV-1 through impaired Fas-dependent killing of infected cells by cytotoxic T cells and through activation of HIV gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis*
  • Caspase 8
  • Caspase 9
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Line
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism*
  • Gene Expression Regulation, Viral
  • HIV Long Terminal Repeat
  • HeLa Cells
  • Herpesvirus 8, Human / metabolism*
  • Humans
  • Molecular Sequence Data
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Sequence Alignment
  • Transfection
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Viral Proteins / physiology*
  • fas Receptor / genetics
  • fas Receptor / metabolism
  • fas Receptor / physiology*

Substances

  • Enzyme Precursors
  • NF-kappa B
  • Viral Proteins
  • fas Receptor
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases