Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
BMC Biol. 2012 Jul 24;10:63. doi: 10.1186/1741-7007-10-63.
B cell lymphoma 2 (Bcl-2) proteins are the central regulators of apoptosis. The two bcl-2 genes in Drosophila modulate the response to stress-induced cell death, but not developmental cell death. Because null mutants are viable, Drosophila provides an optimum model system to investigate alternate functions of Bcl-2 proteins. In this report, we explore the role of one bcl-2 gene in nutrient stress responses.
We report that starvation of Drosophila larvae lacking the bcl-2 gene, buffy, decreases survival rate by more than twofold relative to wild-type larvae. The buffy null mutant reacted to starvation with the expected responses such as inhibition of target of rapamycin (Tor) signaling, autophagy initiation and mobilization of stored lipids. However, the autophagic response to starvation initiated faster in larvae lacking buffy and was inhibited by ectopic buffy. We demonstrate that unusually high basal Tor signaling, indicated by more phosphorylated S6K, was detected in the buffy mutant and that removal of a genomic copy of S6K, but not inactivation of Tor by rapamycin, reverted the precocious autophagy phenotype. Instead, Tor inactivation also required loss of a positive nutrient signal to trigger autophagy and loss of both was sufficient to activate autophagy in the buffy mutant even in the presence of enforced phosphoinositide 3-kinase (PI3K) signaling. Prior to starvation, the fed buffy mutant stored less lipid and glycogen, had high lactate levels and maintained a reduced pool of cellular ATP. These observations, together with the inability of buffy mutant larvae to adapt to nutrient restriction, indicate altered energy metabolism in the absence of buffy.
All animals in their natural habitats are faced with periods of reduced nutrient availability. This study demonstrates that buffy is required for adaptation to both starvation and nutrient restriction. Thus, Buffy is a Bcl-2 protein that plays an important non-apoptotic role to promote survival of the whole organism in a stressful situation.
B 细胞淋巴瘤 2（Bcl-2）蛋白是细胞凋亡的核心调节因子。果蝇中的两个 bcl-2 基因调节应激诱导的细胞死亡的反应，但不调节发育中的细胞死亡。由于缺失突变体是可行的，因此果蝇提供了一个最佳的模型系统来研究 Bcl-2 蛋白的替代功能。在本报告中，我们研究了一个 bcl-2 基因在营养胁迫反应中的作用。
我们报告说，缺乏 bcl-2 基因 buffy 的果蝇幼虫在饥饿时的存活率比野生型幼虫低两倍以上。buffy 缺失突变体对饥饿的反应与预期的反应一致，如抑制雷帕霉素靶蛋白（Tor）信号、自噬起始和储存脂质的动员。然而，buffy 缺失突变体对饥饿的自噬反应更快，并且 buffy 的异位表达抑制了自噬。我们证明，在 buffy 突变体中检测到异常高的基础 Tor 信号，表现为更多的磷酸化 S6K，并且去除 S6K 的一个基因组拷贝，而不是通过 rapamycin 使 Tor 失活，逆转了早熟的自噬表型。相反，Tor 的失活还需要去除一个正向的营养信号来触发自噬，而两者的缺失足以在 buffy 突变体中激活自噬，即使在强制磷酸肌醇 3-激酶（PI3K）信号存在的情况下也是如此。在饥饿之前，饱食的 buffy 突变体储存的脂质和糖原较少，乳酸水平较高，并且细胞内 ATP 池较小。这些观察结果，以及 buffy 突变体幼虫无法适应营养限制，表明在 buffy 缺失的情况下能量代谢发生了改变。
所有在其自然栖息地的动物都面临着营养供应减少的时期。本研究表明，buffy 对于适应饥饿和营养限制都是必需的。因此，Buffy 是一种 Bcl-2 蛋白，在应激情况下对促进整个生物体的生存起着重要的非凋亡作用。
