Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis.
Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis.
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ATM/ATR 磷酸化丝氨酰-tRNA 合成酶对于缺氧诱导的血管生成至关重要
DOI：
10.1371/journal.pbio.3000991
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发表时间：
2020-12
期刊：
影响因子：
9.8
通讯作者：
Yang XL
中科院分区：
文献类型：
--
作者：
Shi Y;Liu Z;Zhang Q;Vallee I;Mo Z;Kishi S;Yang XL
缺氧诱导的血管生成维持组织氧供应，防止缺血，但也促进肿瘤进展和恶性肿瘤。这是通过缺氧诱导因子1 （HIF-1）和c-Myc等转录因子的激活介导的，但缺氧对血管生成负调节因子的影响尚不清楚。在血管发育过程中，seryl-tRNA合成酶（SerRS）通过拮抗c-Myc和转录抑制血管内皮生长因子a （VEGFA）表达的新机制调控血管生成。在这里，我们发现SerRS的转录抑制作用在缺氧条件下通过被共济失调毛细血管扩张突变（ATM）和共济失调毛细血管扩张突变和rad3相关（ATR）在Ser101和Ser241位点磷酸化而失活，从而减弱其DNA结合能力。在斑马鱼中，SerRSS101D/S241D，一种磷酸化模拟突变体，不能抑制VEGFA的表达来支持正常的血管发育。此外，SerRSS101A/S241A（一种磷酸化缺陷和组成型活性突变体）的表达可以阻止缺氧诱导的c-Myc和HIF-1与VEGFA启动子的结合，以及VEGFA表达的激活。一致地，SerRSS101A/S241A强烈抑制小鼠正常和肿瘤来源的血管生成。因此，我们揭示了调控缺氧血管生成的关键步骤，并强调了核SerRS在发育后血管生成调控中的重要性。核SerRS在抑制c-Myc和HIF-1中的作用可能为纠正病理环境下血管生成失调提供治疗机会。
Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression. Here, we reveal that the transcriptional repressor role of SerRS is inactivated under hypoxia through phosphorylation by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and RAD3-related (ATR) at Ser101 and Ser241 to attenuate its DNA binding capacity. In zebrafish, SerRSS101D/S241D, a phosphorylation-mimicry mutant, cannot suppress VEGFA expression to support normal vascular development. Moreover, expression of SerRSS101A/S241A, a phosphorylation-deficient and constitutively active mutant, prevents hypoxia-induced binding of c-Myc and HIF-1 to the VEGFA promoter, and activation of VEGFA expression. Consistently, SerRSS101A/S241A strongly inhibits normal and tumor-derived angiogenesis in mice. Therefore, we reveal a key step regulating hypoxic angiogenesis and highlight the importance of nuclear SerRS in post-developmental angiogenesis regulation in addition to vascular development. The role of nuclear SerRS in inhibiting both c-Myc and HIF-1 may provide therapeutic opportunities to correct dysregulation of angiogenesis in pathological settings.
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