Spermidine/spermine N1-acetyltransferase-1 binds to hypoxia-inducible factor-1α (HIF-1α) and RACK1 and promotes ubiquitination and degradation of HIF-1α
Spermidine/spermine N1-acetyltransferase-1 binds to hypoxia-inducible factor-1α (HIF-1α) and RACK1 and promotes ubiquitination and degradation of HIF-1α
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DOI：
10.1074/jbc.m705627200
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发表时间：
2007-11-16
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 H.;Liu, Ye V.;Semenza, Gregg L.
缺氧诱导因子-1（HIF-1）是氧稳态的主要调节因子，其控制编码在血管生成、红细胞生成和葡萄糖/能量代谢中起关键作用的蛋白质的基因的表达。HIF-1 α亚基的稳定性受泛素化和蛋白酶体降解的调节。在需氧细胞中，HIF-1 α的O-2依赖性脯氨酰羟基化是结合von Hippel-Lindau肿瘤抑制蛋白VHL所必需的，VHL随后募集延伸蛋白C泛素连接酶复合物。SSAT 2（亚精胺/精胺N-乙酰转移酶-2）与HIF-1 α结合并通过稳定VHL和延伸蛋白C的相互作用促进其泛素化/降解。用热休克蛋白HSP 90抑制剂处理细胞诱导HIF-1 α降解，即使在缺氧条件下。HSP 90与RACK 1竞争结合HIF-1 α，HSP 90抑制导致RACK 1结合增加，RACK 1以O-2-非依赖性方式募集延伸蛋白C泛素连接酶复合物与HIF-1 α结合。在这项工作中，我们证明，SSAT 1，其中共享46%的氨基酸同一性与SSAT 2，也结合到HIF-1 α，并促进其泛素化/降解。然而，与SSAT 2相反，SSAT 1通过稳定HIF-1 α与RACK 1的相互作用起作用。因此，旁系同源物SSAT 1和SSAT 2在促进HIF-1 α的O-2非依赖性和O-2依赖性降解中发挥互补作用。
Hypoxia-inducible factor-1 (HIF-1) is a master regulator of oxygen homeostasis that controls the expression of genes encoding proteins that play key roles in angiogenesis, erythropoiesis, and glucose/energy metabolism. The stability of the HIF-1 alpha subunit is regulated by ubiquitination and proteasomal degradation. In aerobic cells, O-2-dependent prolyl hydroxylation of HIF-1 alpha is required for binding of the von Hippel-Lindau tumor suppressor protein VHL, which then recruits the Elongin C ubiquitin-ligase complex. SSAT2 (spermidine/spermine N-acetyltransferase-2) binds to HIF-1 alpha and promotes its ubiquitination/degradation by stabilizing the interaction of VHL and Elongin C. Treatment of cells with heat shock protein HSP90 inhibitors induces the degradation of HIF-1 alpha even under hypoxic conditions. HSP90 competes with RACK1 for binding to HIF-1 alpha, and HSP90 inhibition leads to increased binding of RACK1, which recruits the Elongin C ubiquitin-ligase complex to HIF-1 alpha in an O-2-independent manner. In this work, we demonstrate that SSAT1, which shares 46% amino acid identity with SSAT2, also binds to HIF-1 alpha and promotes its ubiquitination/degradation. However, in contrast to SSAT2, SSAT1 acts by stabilizing the interaction of HIF-1 alpha with RACK1. Thus, the paralogs SSAT1 and SSAT2 play complementary roles in promoting O-2-independent and O-2-dependent degradation of HIF-1 alpha.