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PMID: 10627563 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Alpha/beta interferons potentiate virus-induced apoptosis through activation of the FADD/Caspase-8 death signaling pathway.

Journal of virology ·Vol. 74 ·No. 3 ·2000-02-00 ·Pages 1513-23

Balachandran S, Roberts PC, Kipperman T, Bhalla KN, Compans RW, Archer DR, Barber GN

Abstract

Interferon (IFN) mediates its antiviral effects by inducing a number of responsive genes, including the double-stranded RNA (dsRNA)-dependent protein kinase, PKR. Here we report that inducible overexpression of functional PKR in murine fibroblasts sensitized cells to apoptosis induced by influenza virus, while in contrast, cells expressing a dominant-negative variant of PKR were completely resistant. We determined that the mechanism of influenza virus-induced apoptosis involved death signaling through FADD/caspase-8 activation, while other viruses such as vesicular stomatitis virus (VSV) and Sindbis virus (SNV) did not significantly provoke PKR-mediated apoptosis but did induce cytolysis of fibroblasts via activation of caspase-9. Significantly, treatment with IFN-alpha/beta greatly sensitized the fibroblasts to FADD-dependent apoptosis in response to dsRNA treatment or influenza virus infection but completely protected the cells against VSV and SNV replication in the absence of any cellular destruction. The mechanism by which IFN increases the cells' susceptibility to lysis by dsRNA or certain virus infection is by priming cells to FADD-dependent apoptosis, possibly by regulating the activity of the death-induced signaling complex (DISC). Conversely, IFN is also able to prevent the replication of viruses such as VSV that avoid triggering FADD-mediated DISC activity, by noncytopathic mechanisms, thus preventing destruction of the cell.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Apoptosis Blotting, Western Carrier Proteins/metabolism Caspase 8 Caspase 9 Caspases/metabolism Cell Line Fas-Associated Death Domain Protein Influenza A virus/physiology Interferon-alpha/pharmacology Interferon-beta/pharmacology Mice Protein Serine-Threonine Kinases/metabolism RNA, Double-Stranded/metabolism,pharmacology Signal Transduction Sindbis Virus/physiology Vesicular stomatitis Indiana virus/physiology Virus Replication
Chemicals
Adaptor Proteins, Signal Transducing Carrier Proteins Fadd protein, mouse Fas-Associated Death Domain Protein Interferon-alpha RNA, Double-Stranded Interferon-beta Protein Serine-Threonine Kinases Casp8 protein, mouse Casp9 protein, mouse Caspase 8 Caspase 9 Caspases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Balachandran S
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136, USA.
Roberts P C
Kipperman T
Bhalla K N
Compans R W
Archer D R
Barber G N
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.74.3.1513-1523.2000
Published
2000-02-00
Pages
1513-23
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC111487
Subset
IM
Grants
NCI NIH HHS · R01 CA084247 · United States
NCI NIH HHS · R01-CA84247-01 · United States
NCI NIH HHS · R29-CA72648-01 · United States
External Links
PubMed source DOI: 10.1128/jvi.74.3.1513-1523.2000 PMC Full Text View journal details
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