Filiano Anthony J, Bailey Craig D C, Tucholski Janusz, Gundemir Soner, Johnson Gail V W
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FASEB J. 2008 Aug;22(8):2662-75. doi: 10.1096/fj.07-097709. Epub 2008 Mar 28.
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 1beta (HIF1beta) as a TG2 binding partner. HIF1beta and HIF1alpha 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 HIF1alpha or HIF1beta, 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 HIF1beta, 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.
转谷氨酰胺酶2（TG2）是一种多功能酶，与神经退行性疾病、局部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，我们调查了TG2在细胞对缺血和缺氧反应中的作用。在暴露于氧和葡萄糖剥夺（OGD）的神经元中，TG2表达上调，并且TG2表达增加可保护神经元免受OGD诱导的细胞死亡，这与其转酰胺活性无关。我们确定缺氧诱导因子1β（HIF1β）为TG2结合伴侣。HIF1β和HIF1α共同形成异二聚体转录因子缺氧诱导因子1（HIF1）。在缺氧条件下，TG2和转氨酶失活突变体C277S-TG2抑制了HIF依赖性转录报告基因检测，而不影响HIF1α或HIF1β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OGD诱导的HIF依赖性促凋亡基因Bnip3的上调，但对与促生存过程相关的VEGF表达没有影响。本研究首次证明TG2可保护细胞免受OGD损伤，与HIF1β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延迟的神经元细胞死亡方面发挥重要作用。
