The cellular response to hypoxia is characterised by a switch in the transcriptional program, mediated predominantly by the hypoxia inducible factor family of transcription factors (HIF). Regulation of HIF1 is primarily controlled by post-translational modification of the HIF1α subunit, which can alter its stability and/or activity. This study identifies an unanticipated role for the X-linked inhibitor of apoptosis (XIAP) protein as a regulator of Lys⁶³-linked polyubiquitination of HIF1α. Lys⁶³-linked ubiquitination of HIF1α by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys⁶³-linked polyubiquitination promotes HIF1α nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys⁶³-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1α, promoter occupancy, HIF-dependent gene expression and cell viability. Our data reveals an additional and significant level of control of the HIF1 by XIAP, with important implications in understanding the role of HIF1 and XIAP in human disease.

中文翻译：

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XIAP通过针对Lys ⁶³连锁的多泛素化作用的HIF1α来上调HIF靶基因的表达

细胞对缺氧的反应的特征是转录程序中的开关，主要由转录因子的低氧诱导因子家族（HIF）介导。HIF1的调节主要受HIF1α亚基的翻译后修饰控制，这可以改变其稳定性和/或活性。这项研究确定了X连锁的凋亡抑制剂（XIAP）蛋白作为Lys ⁶³连锁的HIF1α的多聚泛素调节剂的意外作用。XIAP与Lys ⁶³连锁的HIF1α泛素化取决于E2泛素结合酶Ubc13的活性。我们发现XIAP和Ubc13依赖的Lys ⁶³链多聚泛素化促进HIF1α核保留，从而导致HIF1反应基因的表达增加。与Lys ⁶³相连的多聚泛素化途径的抑制导致核HIF1α水平降低，启动子占有，HIF依赖性基因表达和细胞活力降低。我们的数据显示，XIAP对HIF1的控制水平更高，对理解HIF1和XIAP在人类疾病中的作用具有重要意义。