Surveillance-Activated Defenses Block the ROS–Induced Mitochondrial Unfolded Protein Response

Disturbance of cellular functions results in the activation of stress-signaling pathways that aim at restoring homeostasis. We performed a genome-wide screen to identify components of the signal transduction of the mitochondrial unfolded protein response (UPRmt) to a nuclear chaperone promoter. We used the ROS generating complex I inhibitor paraquat to induce the UPRmt, and we employed RNAi exposure post-embryonically to allow testing genes whose knockdown results in embryonic lethality. We identified 54 novel regulators of the ROS–induced UPRmt. Activation of the UPRmt, but not of other stress-signaling pathways, failed when homeostasis of basic cellular mechanisms such as translation and protein transport were impaired. These mechanisms are monitored by a recently discovered surveillance system that interprets interruption of these processes as pathogen attack and depends on signaling through the JNK-like MAP-kinase KGB-1. Mutation of kgb-1 abrogated the inhibition of ROS–induced UPRmt, suggesting that surveillance-activated defenses specifically inhibit the UPRmt but do not compromise activation of the heat shock response, the UPR of the endoplasmic reticulum, or the SKN-1/Nrf2 mediated response to cytosolic stress. In addition, we identified PIFK-1, the orthologue of the Drosophila PI 4-kinase four wheel drive (FWD), and found that it is the only known factor so far that is essential for the unfolded protein responses of both mitochondria and endoplasmic reticulum. This suggests that both UPRs may share a common membrane associated mechanism.

细胞功能紊乱会激活旨在恢复体内稳态的应激信号通路。我们开展了全基因组筛选，以鉴定介导线粒体未折叠蛋白反应（mitochondrial unfolded protein response, UPRmt）向核伴侣蛋白启动子转导信号的组分。我们使用产生活性氧（reactive oxygen species, ROS）的复合物I抑制剂百草枯诱导UPRmt，并在胚胎发育后期施加RNA干扰（RNAi），以此来探究那些敲低会导致胚胎致死的基因。我们共鉴定出54个ROS诱导型UPRmt的新型调控因子。当翻译与蛋白质转运等基础细胞机制的稳态遭到破坏时，UPRmt的激活会受到阻碍，但其他应激信号通路的激活则不受此影响。这类基础细胞机制会受到一套新近发现的监控系统的调控：该系统会将这些过程的中断识别为病原体侵袭，且依赖于JNK样丝裂原活化蛋白激酶KGB-1介导的信号转导。kgb-1基因的突变会解除对ROS诱导型UPRmt的抑制，这表明该监控系统激活的防御反应会特异性抑制UPRmt，但不会影响热休克反应、内质网未折叠蛋白反应，或是SKN-1/Nrf2介导的胞质应激反应的激活。此外，我们还鉴定出果蝇磷脂酰肌醇4-激酶四轮驱动（four wheel drive, FWD）的同源蛋白PIFK-1，并发现在目前已知的因子中，它是唯一同时对线粒体与内质网的未折叠蛋白反应必不可少的蛋白。这一结果提示，两种未折叠蛋白反应可能共享一套膜相关的共同机制。