SARS-CoV-2 基因组复制
中文名称
通路描述
该 COVID-19 通路结合了来自 SARS-CoV-1 数据的计算推断（https://reactome.org/documentation/inferred-events）和手动校订，具体描述见 SARS-CoV-2 整体感染通路的汇总。直接研究的步骤包括 RTC 结合 RNA 模板、nsp12 的聚合酶活性（Hillen et al. 2020, Wang et al. 2020, Yin et al. 2020）、nsp13 的解旋酶活性（Chen et al. 2020, Ji et al. 2020, Shu et al. 2020）、nsp16 的加帽活性（Viswanathan et al. 2020）以及 SARS-CoV-2 基因组 RNA 的 polyadenylation（Kim et al. 2020）。复制发生在由 ER 膜扭曲形成的双膜囊泡（DMVs）中（Cortese et al, 2020; Snijder et al, 2020）。形成这些复制器器的一个宿主因子是磷脂酰肌酸（Tabata et al, 2021）。其他步骤是从 SARS-CoV-1 及相关冠状病毒的先前研究中推断的。人类 SARS-CoV-1 的 plus 链 RNA 基因组由由非结构蛋白 nsp3-nsp16 组成的病毒复制 - 转录复合物（RTC）复制，该复合物由开放阅读框 ORF1a 和 ORF1b 编码。两个 RTC 蛋白 nsp8 和 nsp12 具有 5'-3' RNA 依赖的 RNA 聚合酶活性。nsp12 是主要的 RNA 聚合酶，而 nsp8 被认为作为 RNA 引物酶起作用。nsp14 作为 3'-5' 外切酶，增加了 RTC 的保真度。nsp14 还具有 RNA 加帽活性，与 nsp16 协同作用，为病毒 plus 链和 minus 链基因组及亚基因组 RNA 加帽，从而通过使它们能够逃避免疫介导的宿主先天免疫反应而赋予病毒 RNA 稳定性。nsp13 是 RNA 解旋酶，被认为在复制和转录期间熔解基因组 RNA 中的二级结构。plus 链基因组 RNA 首先用于合成 minus 链基因组 RNA 互补体，随后作为模板合成 plus 链病毒 RNA 基因组，这些基因组被包装到成熟的病毒颗粒中。如需综述，请参考 Yang and Leibowitz 2015, Snijder et al. 2016, Fung and Liu 2019。
英文描述
Cellular response to hypoxia Oxygen plays a central role in the functioning of human cells: it is both essential for normal metabolism and toxic. Here we have annotated one aspect of cellular responses to oxygen, the role of hypoxia-inducible factor in regulating cellular transcriptional responses to changes in oxygen availability.In the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) and on asparagine residues by HIF1AN (FIH) (reviewed in Pouyssegur et al. 2006, Semenza 2007, Kaelin and Ratcliffe 2008, Nizet and Johnson 2009, Brahimi-Horn and Pouyssegur 2009, Majmundar et al. 2010, Loenarz and Schofield 2011). Both types of reaction require molecular oxygen as a substrate and it is probable that at least some HIF-alpha molecules carry both hydroxylated asparagine and hydroxylated proline (Tian et al. 2011).
Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF.
Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF.
所含基因
4 个基因