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李颖, 毕健玲, 王丁, 肖武汉. PHD2基因在鲸类低氧信号通路中的功能[J]. 水生生物学报, 2023, 47(5): 767-774. DOI: 10.7541/2023.2019.261
引用本文: 李颖, 毕健玲, 王丁, 肖武汉. PHD2基因在鲸类低氧信号通路中的功能[J]. 水生生物学报, 2023, 47(5): 767-774. DOI: 10.7541/2023.2019.261
LI Ying, BI Jian-Ling, WANG Ding, XIAO Wu-Han. PRIMARY ANALYSIS OF PHD2 FROM THREE DIFFERENT CETACEANS IN HYPOXIA SIGNAL PATHWAY[J]. ACTA HYDROBIOLOGICA SINICA, 2023, 47(5): 767-774. DOI: 10.7541/2023.2019.261
Citation: LI Ying, BI Jian-Ling, WANG Ding, XIAO Wu-Han. PRIMARY ANALYSIS OF PHD2 FROM THREE DIFFERENT CETACEANS IN HYPOXIA SIGNAL PATHWAY[J]. ACTA HYDROBIOLOGICA SINICA, 2023, 47(5): 767-774. DOI: 10.7541/2023.2019.261

PHD2基因在鲸类低氧信号通路中的功能

PRIMARY ANALYSIS OF PHD2 FROM THREE DIFFERENT CETACEANS IN HYPOXIA SIGNAL PATHWAY

  • 摘要: 为研究鲸类低氧适应的分子机制, 文章克隆了不同低氧耐受能力的3个鲸类物种, 抹香鲸(Physeter macrocephalus)、白鲸(Delphinapterus leucas)和长江江豚(Neophocaena phocaenoids asiaeorientalis)的脯氨酸羟化酶2(PHD2)。通过对其序列进行分析, 发现3个物种PHD2的氨基酸序列非常保守。通过对这3个物种的PHD2的功能进行探究发现: 3个物种的PHD2在常氧情况下均可以降解3个物种的HIF-α(包括HIF-1α和HIF-2α)蛋白, 而在低氧(O2浓度小于2%)情况下, PHD2则无法明显降解HIF-α蛋白。在常氧下, 鲸类的PHD2降解HIF-α是依赖于识别鲸类的HIF-1α上LTLLAP和LEMLAP, HIF-2α的LAQLAP和LETLAP氨基酸片段, 推测PHD2是通过对HIF-α序列中的脯氨酸位点进行羟基化修饰后, 被VHL-E3泛素连接酶复合体所识别, 发生泛素化降解。而在低氧条件下, PHD2的活性受到抑制HIF-α不能被VHL-E3泛素连接酶复合体识别, 发生降解。研究对3种不同低氧耐受能力的鲸的PHD2功能进行初步探究, 发现3种鲸的PHD2在降解HIF-α(HIF-1αHIF-2α)的功能与已报道人PHD2功能相似。研究结果为更深入研究鲸类的PHD2HIF的复杂反馈调控提供依据, 为脯氨酸羟化酶家族(PHDs)其他成员与HIF相互作用提供重要的参考资料, 也为深入研究鲸类的低氧耐受提供基础。

     

    Abstract: Hypoxia was a major challenge faced by cetaceans during the process of prolonged diving in the secondary aquatic adaption. Although physiological and anatomical traits of hypoxia tolerance of cetaceans have been well characterized, the molecular basic behind their adaption remain unknown. Proline hydroxylase domain enzyme 2 (PHD2), one of the pivotal regulators of the molecular response in hypoxic stress, can utilize oxygen to hydroxylate and mediate the stability and transcriptional activity of the alpha submit of HIF. In this study, the PHD2 gene was cloned from three species with different duration, the sperm whale (Physeter macrocephalus), the beluga whale (Delphinapterus leucas), and the Yangtze finless porpoise (Neophocaena phocaenoids asiaeorientalis). Sequence analyses revealed that the sequences of PHD2 from these three species were highly evolutionarily conserved, with few deletions and substitutions. In addition, we analyzed PHD2 in these three species in the hypoxia signaling pathway. Under normoxia, PHD2 of three species can degrade HIF-α (including HIF-1α and HIF-2α) protein of three species. Under hypoxia (O2 concentration less than 2%), the HIF-α proteins can accumulate. Furthermore, the degradation of HIF-α by PHD2 in cetaceans is relying on the recognition of the amino acid motif LTLLAP and LEMLAP on HIF-1α, the LAQLAP and LETLAP amino acid motif of HIF-2α, as well as the proline hydroxylase efficiency of PHD2. It is speculated that PHD2 use oxygen as a substrate to hydroxylate designated proline residues within the conserved motif LXXLAP of HIF-1α and HIF-2α, allowing von Hippel-Lindau protein (pVHL), the substrate recognition component of an E3 ubiquitin ligase complex, to bind to hydroxylated HIF-1α and HIF-2α and target them for proteasomal degradation. Without the oxygen, the activity of PHD2 is restrained and the function is not fully utilized. This study is a preliminary exploration on the PHD2 function of three different hypoxia-tolerant whales, aiming to provide a basis for further study of the complex feedback regulation of PHD2 and HIF. Future investigations on another PHD isoforms over HIF pathways are able to be achieved. Thus, it also provide the basis for in-depth study on adaptive mechanisms of hypoxic tolerance in cetaceans.

     

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