SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases
SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases
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DOI：
10.1016/j.celrep.2016.08.031
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发表时间：
2016-09-13
期刊：
影响因子：
8.8
通讯作者：
Mueller, Stefan
中科院分区：
文献类型：
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作者：
Kunz, Kathrin;Wagner, Kristina;Mueller, Stefan
泛素样SUMO修饰物对蛋白质的翻译后修饰是一个严格调控的高度动态过程。SUMO特异性异肽酶的SENP家族包括六种半胱氨酸蛋白酶。它们有助于平衡相扑共轭，但它们的调节还不清楚。我们证明，在缺氧细胞提取物中，SENP家族成员的催化活性，特别是SENP 1和SENP 3，在一个快速和完全可逆的过程中被抑制。比较质谱法从常氧和缺氧细胞定义了一个子集的缺氧诱导的SUMO 1的目标，包括SUMO连接酶RanBP 2和PIAS 2，葡萄糖转运蛋白1，和转录调节因子。在最强烈的诱导目标，我们确定了转录辅阻遏BHLHE 40，它控制缺氧基因表达程序。我们提供的证据表明，SUMO化的BHLHE 40逆转SENP 1，并有助于转录抑制的代谢主调节基因PGC-1 α。我们提出了一个途径，连接氧控制SENP活性缺氧重编程代谢。
Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1 alpha. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.