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

PLoS One. 2020 Jan 30;15(1):e0228441. doi: 10.1371/journal.pone.0228441. eCollection 2020.

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 (cFLIPlong and cFLIPshort) which determine cell death and survival. Interestingly, several viruses encode FLIP proteins, homologous to cFLIPshort, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 8 / metabolism*
  • Cell Proliferation
  • Gene Deletion
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / metabolism*
  • Humans
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism
  • Mice
  • Models, Animal
  • Viral Proteins / genetics
  • Viral Proteins / metabolism

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Viral Proteins
  • Casp8 protein, mouse
  • Caspase 8

Grants and funding

This work received funding from the DFG projects SFB796 (B07, B09) to CB, MS and MFN, SFB1181 (B02, C05) to CB and MFN, TRR241 (A02, A03, A06, C04) to CB, MS, CG, and MFN, SPP1656 to CB, CG, and MFN, KFO257 (TP01, TP05, TP08) to CB, MS, and MFN, the FOR2438 (P2, P5, P8) to CB, MS, and MFN, FOR2886 (A02) to CG and individual grants BE3686/2 to CB and GU 1431/1-2 to CG. Furthermore the work was supported by the Interdisciplinary Centre for Clinical Research (IZKF, J78, P056, A75) of the University Erlangen-Nürnberg to BR and CG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.