Stimulus-dependent and domain-dependent cell death acceleration by an IFN-inducible protein, human MxA.
Human MxA is an interferon- alpha / beta (IFN-alpha/beta)-inducible protein that inhibits multiplication of influenza viruses and other RNA viruses. We reported that MxA accelerates cell death induced by apoptotic stimuli as well as influenza viral infection. However, the mechanism of MxA-mediated enhancement of cell death is not well understood. Here, we demonstrated that the cell death promotion activity of MxA was caspase dependent when cell death was induced by UV irradiation or cycloheximide (CHX). In contrast, in the case of cell death after influenza viral infection, MxA promoted both caspase-dependent and caspase-independent cell death. The C-terminal region of MxA containing the oligomerization domain was found to be responsible for promotion of the cell death induced by CHX. In the case of cell death after influenza viral infection, both C-terminal and N-terminal regions were shown to be involved in cell death promotion, although the GTP-binding and GTP-hydrolysis activity dependent on a tripartite GTP-binding motif in the N-terminal region was not required for the cell death promotion activity of MxA. These results suggest that MxA accelerates cell death induced by influenza viral infection through at least two distinct pathways.
Numajiri
Akiko
A
Department of Infection Biology, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
Mibayashi
Masaki
M
Nagata
Kyosuke
K
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003513:Cycloheximide / Q000633:toxicity; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D051379:Mice; D064547:Myxovirus Resistance Proteins; D017434:Protein Structure, Tertiary / Q000235:genetics; D041701:Swiss 3T3 Cells; D014466:Ultraviolet Rays
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D006160:Guanosine Triphosphate; D003513:Cycloheximide; D020169:Caspases; D019204:GTP-Binding Proteins