Transglutaminase 2 protects against ischemic insult, interacts with HIF1β, and attenuates HIF1 signaling
Transglutaminase 2 protects against ischemic insult, interacts with HIF1β, and attenuates HIF1 signaling
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DOI：
10.1096/fj.07-097709
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Johnson, Gail V. W.
中科院分区：
文献类型：
--
作者：
Filiano, Anthony J.;Bailey, Craig D. C.;Johnson, Gail V. W.
转谷氨酰胺酶 2 (TG2) 是一种多功能酶，与神经退行性疾病、缺血和中风的发病机制有关。 TG2 调节疾病进展的机制尚未阐明。在本研究中，我们研究了 TG2 在细胞对缺血和缺氧的反应中的作用。 TG2 在暴露于缺氧和缺糖 (OGD) 的神经元中上调，并且增加的 TG2 表达可以保护神经元免受 OGD 诱导的细胞死亡，而与其转酰胺基活性无关。我们确定缺氧诱导因子 1 beta (HIF1 beta) 作为 TG2 结合伴侣。 HIF1β 和 HIF1α 一起形成异二聚体转录因子缺氧诱导因子 1（HIF1）。 TG2 和转氨酶失活突变体 C277S-TG2 在缺氧条件下抑制 HIF 依赖性转录报告基因测定，而不影响 HIF1 α 或 HIF1 β 的核蛋白水平、它们形成 HIF1 异二聚体转录因子的能力或 HIF1 与其 DNA 反应元件的结合。有趣的是，TG2 减弱了 HIF 依赖性促凋亡基因 Bnip3 对 OGD 的上调，但对 VEGF 的表达没有影响，而 VEGF 与促存活过程有关。这项研究首次证明 TG2 可以预防 OGD，与 HIF1 β 相互作用，并减弱 HIF1 缺氧反应途径。这些结果表明，TG2 可能在预防缺血和中风中迟发性神经元细胞死亡方面发挥重要作用。
Transglutaminase 2 (TG2) is a multifunctional enzyme that has been implicated in the pathogenesis of neurodegenerative diseases, ischemia, and stroke. The mechanism by which TG2 modulates disease progression have not been elucidated. In this study we investigate the role of TG2 in the cellular response to ischemia and hypoxia. TG2 is up-regulated in neurons exposed to oxygen and glucose deprivation (OGD), and increased TG2 expression protects neurons against OGD-induced cell death independent of its transamidating activity. We identified hypoxia inducible factor 1 beta (HIF1 beta) as a TG2 binding partner. HIF1 beta and HIF1 alpha together form the heterodimeric transcription factor hypoxia inducible factor 1(HIF1). TG2 and the transaminase-inactive mutant C277S-TG2 inhibited a HIF-dependent transcription reporter assay under hypoxic conditions without affecting nuclear protein levels for HIF1 alpha or HIF1 beta, their ability to form the HIF1 heterodimeric transcription factor, or HIF1 binding to its DNA response element. Interestingly, TG2 attenuates the up-regulation of the HIF-dependent proapoptotic gene Bnip3 in response to OGD but had no effect on the expression of VEGF, which has been linked to prosurvival processes. This study demonstrates for the first time that TG2 protects against OGD, interacts with HIF1 beta, and attenuates the HIF1 hypoxic response pathway. These results indicate that TG2 may play an important role in protecting against the delayed neuronal cell death in ischemia and stroke.