亚精胺/精胺-N1-乙酰基转移酶2是调节缺氧诱导因子1α的泛素连接酶复合物的重要组成部分。

Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1alpha.

作者信息

Baek Jin Hyen, Liu Ye V, McDonald Karin R, Wesley Jacob B, Hubbi Maimon E, Byun Hweejo, Semenza Gregg L

机构信息

Vascular Biology Program, Institute for Cell Engineering, Department of Pediatrics, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

出版信息

J Biol Chem. 2007 Aug 10;282(32):23572-80. doi: 10.1074/jbc.M703504200. Epub 2007 Jun 8.

DOI:10.1074/jbc.M703504200

PMID:17558023

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that functions as a master regulator of oxygen homeostasis. The HIF-1alpha 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-1alpha, VHL, and Elongin C and promotes ubiquitination of hydroxylated HIF-1alpha 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-1alpha that is observed in oxygenated cells.

摘要

缺氧诱导因子1（HIF-1）是一种异源二聚体转录因子，作为氧稳态的主要调节因子发挥作用。HIF-1α亚基会发生依赖于O₂的脯氨酰羟化，导致被冯·希佩尔-林道蛋白（VHL）-延伸蛋白C泛素连接酶复合物泛素化，并被26S蛋白酶体降解。在本研究中，我们证明亚精胺/精胺-N¹-乙酰基转移酶（SSAT）2在此过程中起关键作用。SSAT2与HIF-1α、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-1α的泛素化。SSAT2的多价相互作用提供了一种机制，以确保高效形成复合物，这对于在含氧细胞中观察到的HIF-1α极其快速的泛素化和降解是必要的。