Lewis J, Oyler G A, Ueno K, Fannjiang Y R, Chau B N, Vornov J, Korsmeyer S J, Zou S, Hardwick J M
Department of Pharmacology and Molecular Sciences, Johns Hopkins University Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
Nat Med. 1999 Jul;5(7):832-5. doi: 10.1038/10556.
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.
Bax蛋白作为促凋亡的Bcl-2家族成员广为人知，过表达时可在多种细胞类型中引发凋亡，对神经元的发育性细胞死亡很重要。然而，在此研究中发现，Bax在感染辛德毕斯病毒的小鼠中是神经元细胞死亡的有效抑制剂。新生小鼠对嗜神经性辛德毕斯病毒的致命感染高度易感，当感染编码Bax的重组辛德毕斯病毒时，可显著免受神经元凋亡和致命疾病的影响。模拟切割后的Bax缺失N端，可使其在体内转变为促凋亡因子。随着小鼠在出生后的第一周内逐渐成熟，它们对致命的辛德毕斯病毒感染获得了抵抗力。然而，与对照同窝小鼠相比，Bax基因敲除小鼠对致命疾病仍然非常敏感，这表明内源性Bax作为一种存活因子发挥作用，并有助于对辛德毕斯病毒诱导的死亡产生年龄依赖性抗性。Bax的保护作用在培养的海马神经元中得以重现，但在培养的背根神经节神经元中未出现。这些发现表明，细胞特异性因子决定了Bax的抗凋亡与促凋亡功能。
