Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195.
Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195
Genetics. 2019 Oct;213(2):481-490. doi: 10.1534/genetics.119.302326. Epub 2019 Aug 1.
Hydrogen sulfide (HS) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, HS is also toxic, and unregulated accumulation or exposure to environmental HS can be lethal. In , the hypoxia inducible factor () coordinates the initial transcriptional response to HS, and is essential to survive exposure to low concentrations of HS. We performed a forward genetic screen to identify mutations that suppress the lethality of mutant animals in HS. The mutations we recovered are specific for HS, as they do not suppress embryonic lethality or reproductive arrest of mutant animals in hypoxia, nor can they prevent the death of mutant animals exposed to hydrogen cyanide. The majority of suppressor mutations we recovered activate the /Nrf2 transcription factor. Activation of SKN-1 by suppressor mutations increased the expression of a subset of HS-responsive genes, consistent with previous findings that plays a role in the transcriptional response to HS. Using transgenic rescue, we show that overexpression of a single gene, , is sufficient to protect mutant animals in HS. The gene encodes a predicated O-acyltransferase enzyme that has previously been shown to negatively regulate HIF-1 activity. Our data indicate that RHY-1 has novel, independent, function that promotes survival in HS.
硫化氢 (HS) 是一种内源性产生的信号分子，具有细胞保护作用，尤其在缺血/再灌注损伤的情况下。然而，HS 也是有毒的，不受调节的积累或暴露于环境 HS 可能是致命的。在 ，缺氧诱导因子 (HIF) 协调对 HS 的初始转录反应，对于在低浓度 HS 下生存至关重要。我们进行了正向遗传筛选，以鉴定出可抑制 HS 中 突变体动物致死性的突变。我们恢复的突变是特异性针对 HS 的，因为它们不能抑制缺氧中 突变体动物的胚胎致死性或生殖阻滞，也不能防止暴露于氰化氢的 突变体动物死亡。我们恢复的大多数 抑制突变激活 /Nrf2 转录因子。通过 抑制突变激活 SKN-1 增加了一组 HS 反应基因的表达，这与先前发现 在 HS 的转录反应中起作用的结果一致。通过转基因拯救，我们表明过表达单个基因 足以保护 HS 中的 突变体动物。该 基因编码一种推定的 O-酰基转移酶，先前已显示其负调控 HIF-1 活性。我们的数据表明，RHY-1 具有促进 HS 中存活的新的、独立的功能。
