Inhibition of virus-induced neuronal apoptosis by Bax.
The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when overexpressed can trigger apoptosis in multiple cell types and is important for the developmental cell death of neurons. However, Bax was found here to be a potent inhibitor of neuronal cell death in mice infected with Sindbis virus. Newborn mice, which are highly susceptible to a fatal infection with neurotropic Sindbis virus, were significantly protected from neuronal apoptosis and fatal disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro-apoptotic factor in vivo. As mice mature during the first week after birth, they acquire resistance to a fatal Sindbis virus infection. However, Bax-deficient mice remained very sensitive to fatal disease compared with their control littermates, indicating that endogenous Bax functions as a survival factor and contributes to age-dependent resistance to Sindbis virus-induced mortality. The protective effects of Bax were reproduced in cultured hippocampal neurons but not in cultured dorsal root ganglia neurons. These findings indicate that cell-specific factors determine the anti-apoptotic versus pro-apoptotic function of Bax.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
J
J
Lewis
G A
GA
Oyler
K
K
Ueno
Y R
YR
Fannjiang
B N
BN
Chau
J
J
Vornov
S J
SJ
Korsmeyer
S
S
Zou
J M
JM
Hardwick
D018354:Alphavirus Infections / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000473:pathology* / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology / Q000821:virology; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology / Q000502:physiology / Q000821:virology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology* / Q000502:physiology / Q000821:virology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D012845:Sindbis Virus / Q000302:isolation & purification / Q000472:pathogenicity*; D014162:Transfection; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein