Inhibition of NF-kappa B activity and cFLIP expression contribute to viral-induced apoptosis.
Virus-induced activation of nuclear factor-kappa B (NF-kappaB) is required for Type 3 (T3) reovirus-induced apoptosis. We now show that NF-kappaB is also activated by the prototypic Type 1 reovirus strain Lang (T1L), which induces significantly less apoptosis than T3 viruses, indicating that NF-kappaB activation alone is not sufficient for apoptosis in reovirus-infected cells. A second phase of virus-induced NF-kappaB regulation, where NF-kappaB activation is inhibited at later times following infection with T3 Abney (T3A), is absent in T1L-infected cells. This suggests that inhibition of NF-kappaB activation at later times post infection also contributes to reovirus-induced apoptosis. Reovirus-induced inhibition of stimulus-induced activation of NF-kappaB is significantly associated with apoptosis following infection of HEK293 cells with reassortant reoviruses and is determined by the T3 S1 gene segment, which is also the primary determinant of reovirus-induced apoptosis. Inhibition of stimulus-induced activation of NF-kappaB also occurs following infection of primary cardiac myocytes with apoptotic (8B) but not non-apoptotic (T1L) reoviruses. Expression levels of the NF-kappaB-regulated cellular FLICE inhibitory protein (cFLIP) reflect NF-kappaB activation in reovirus-infected cells. Further, inhibition of NF-kappaB activity and cFLIP expression promote T1L-induced apoptosis. These results demonstrate that inhibition of stimulus-induced activation of NF-kappaB and the resulting decrease in cFLIP expression promote reovirus-induced apoptosis.
Clarke
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P
Department of Neurology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Penny.Clarke@uchsc.edu
Debiasi
R L
RL
Meintzer
S M
SM
Robinson
B A
BA
Tyler
K L
KL
D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D030102:Orthoreovirus, Mammalian / Q000502:physiology*; D016865:Reassortant Viruses / Q000502:physiology; D012088:Reoviridae Infections / Q000503:physiopathology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B