Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1α
Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1α
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DOI：
10.1074/jbc.m703504200
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发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Baek, Jin Hyen;Liu, Ye V.;Semenza, Gregg L.
缺氧诱导因子1（HIF-1）是一种异源二聚体转录因子，是氧稳态的主要调节因子。HIF-1亚基经历O-2依赖性脯氨酰羟基化，导致von Hippel-Lindau蛋白（VHL）-延伸蛋白C泛素连接酶复合物的泛素化和26 S蛋白酶体的降解。在这项研究中，我们证明了亚精胺/精胺-N-1-乙酰转移酶（SSAT）2在这个过程中起着至关重要的作用。SSAT 2与HIF-1 α、VHL和延伸蛋白C结合，并通过稳定VHL和延伸蛋白C的相互作用促进羟基化HIF-1 α的泛素化。SSAT 2的多价相互作用提供了确保有效复合物形成的机制，这对于在氧合细胞中观察到的HIF-1 α的极其快速的泛素化和降解是必要的。
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that functions as a master regulator of oxygen homeostasis. The HIF-1 subunit is subjected to O-2-dependent prolyl hydroxylation leading to ubiquitination by the von Hippel-Lindau protein (VHL)-Elongin C ubiquitin-ligase complex and degradation by the 26 S proteasome. In this study, we demonstrate that spermidine/spermine-N-1-acetyltransferase (SSAT) 2 plays an essential role in this process. SSAT2 binds to HIF-1 alpha, VHL, and Elongin C and promotes ubiquitination of hydroxylated HIF-1 alpha by stabilizing the interaction of VHL and Elongin C. Multivalent interactions by SSAT2 provide a mechanism to ensure efficient complex formation, which is necessary for the extremely rapid ubiquitination and degradation of HIF-1 alpha that is observed in oxygenated cells.