Department of Entomology, The University of Georgia, Athens, GA 30602.
Department of Entomology, The University of Georgia, Athens, GA 30602
Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):457-465. doi: 10.1073/pnas.1719063115. Epub 2018 Jan 3.
Gut microbes positively affect the physiology of many animals, but the molecular mechanisms underlying these benefits remain poorly understood. We recently reported that bacteria-induced gut hypoxia functions as a signal for growth and molting of the mosquito In this study, we tested the hypothesis that transduction of a gut hypoxia signal requires hypoxia-induced transcription factors (HIFs). Expression studies showed that HIF-α was stabilized in larvae containing bacteria that induce gut hypoxia but was destabilized in larvae that exhibit normoxia. However, we could rescue growth of larvae exhibiting gut normoxia by treating them with a prolyl hydroxylase inhibitor, FG-4592, that stabilized HIF-α, and inhibit growth of larvae exhibiting gut hypoxia by treating them with an inhibitor, PX-478, that destabilized HIF-α. Using these tools, we determined that HIF signaling activated the insulin/insulin growth factor pathway plus select mitogen-activated kinases and inhibited the adenosine monophosphate-activated protein kinase pathway. HIF signaling was also required for growth of the larval midgut and storage of neutral lipids by the fat body. Altogether, our results indicate that gut hypoxia and HIF signaling activate multiple processes in larvae, with conserved functions in growth and metabolism.
肠道微生物对许多动物的生理机能有积极影响，但这些益处背后的分子机制仍知之甚少。我们最近报道称，细菌诱导的肠道缺氧可作为蚊子生长和蜕皮的信号。在这项研究中，我们检验了这样一个假设，即肠道缺氧信号的转导需要缺氧诱导转录因子（HIFs）。表达研究表明，在含有诱导肠道缺氧细菌的幼虫中，HIF-α 得到稳定，但在表现出正常氧合的幼虫中，HIF-α 则不稳定。然而，我们可以通过用脯氨酰羟化酶抑制剂 FG-4592 处理表现出肠道正常氧合的幼虫来挽救它们的生长，该抑制剂稳定了 HIF-α，并用 HIF-α 不稳定的抑制剂 PX-478 处理表现出肠道缺氧的幼虫来抑制它们的生长。使用这些工具，我们确定 HIF 信号激活了胰岛素/胰岛素样生长因子途径加上一些有丝分裂原激活的蛋白激酶，并抑制了腺苷单磷酸激活蛋白激酶途径。HIF 信号对于幼虫中肠的生长和脂肪体中中性脂质的储存也是必需的。总的来说，我们的结果表明，肠道缺氧和 HIF 信号激活了幼虫中的多个过程，在生长和代谢方面具有保守功能。
