Competition through Dimerization between Antiapoptotic and Proapoptotic HS-1-associated Protein X-1 (Hax-1)
Competition through Dimerization between Antiapoptotic and Proapoptotic HS-1-associated Protein X-1 (Hax-1)
复制标题
DOI：
10.1074/jbc.m113.536151
复制
发表时间：
2014-02-07
影响因子：
4.8
通讯作者：
Kontrogianni-Konstantopoulos, Aikaterini
中科院分区：
文献类型：
--
作者：
Koontz, Jason;Kontrogianni-Konstantopoulos, Aikaterini
背景：Hax-1 是一个凋亡调节因子家族。原型变体1具有抗凋亡功能。结果：Hax-1 变体 2 促进细胞死亡，并可以消除变体 1 的保护作用。结论：抗凋亡和促凋亡 Hax-1 变体的比例可能通过隔离或失活来决定细胞命运。意义：Hax-1的不同剪接变体在调节细胞凋亡中具有相反的作用。对Hax-1的研究主要集中在变体(v) 1上，证明了其抗凋亡特性。然而，HAX1 被大量剪接，产生结构不同的亚型。我们试图表征损伤前后大鼠心脏中表达的 Hax-1 亚型。我们证实健康大鼠心肌中至少存在四个 Hax-1 转录本。这些在心肌梗塞诱导前后表现出差异表达，其中v2在转录水平上调12倍，在心肌梗塞后蛋白质水平上调1.5倍。与抗凋亡大鼠和人 v1 相反，与对照载体相比，上皮细胞中大鼠 v2 或人 v4（大鼠 v2 的人同源物）的过表达在 H2O2 处理后使细胞死亡加剧了 30%。大鼠v1和v2或人v1和v4的共表达通过调节细胞色素c释放来中和大鼠和人v1的保护作用以及大鼠v2和人v4的促凋亡作用。这至少部分是由 Hax-1 蛋白形成同型和异型二聚体的能力介导的，其结合亲和力范围从 v1 二聚体约 3.8 nm 到 v1/v2 二聚体约 97 nm。支持这些相互作用的最小结合区位于氨基酸 97-278 之间，几乎所有 Hax-1 蛋白都共享这些区域，表明其他因素调节 Hax-1 同二聚体或异二聚体的优先形成。我们的研究首次表明 Hax-1 是一个抗凋亡和促凋亡调节因子家族，可以通过同源或异源二聚化调节细胞的存活和死亡。
Background: Hax-1 is a family of apoptotic regulators. The prototypical variant 1 has an antiapoptotic function. Results: Hax-1 variant 2 promotes cell death and can abrogate the protective effect of variant 1. Conclusion: The ratio of anti- and proapoptotic Hax-1 variants is likely to determine cell fate via sequestration or inactivation. Significance: Different splice variants of Hax-1 have opposing roles in regulating apoptosis.Studies on Hax-1 have mainly focused on variant (v) 1, demonstrating its antiapoptotic properties. However, HAX1 is heavily spliced, generating structurally distinct isoforms. We sought to characterize the Hax-1 isoforms expressed in rat heart before and after insult. We confirmed the presence of at least four Hax-1 transcripts in healthy rat cardiac muscle. These exhibited differential expression before and after induction of myocardial infarction, with v2 being up-regulated 12-fold at the transcript level and 1.5-fold at the protein level post-insult. Contrary to antiapoptotic rat and human v1, overexpression of rat v2 or human v4 (the human homologue of rat v2) in epithelial cells exacerbated cell death by 30% following H2O2 treatment compared with control vector. Coexpression of rat v1 and v2 or human v1 and v4 neutralized the protective effects of rat and human v1 and the proapoptotic effects of rat v2 and human v4 by modulating cytochrome c release. This is, at least partly, mediated by the ability of Hax-1 proteins to form homotypic and heterotypic dimers with binding affinities ranging from approximate to 3.8 nm for v1 dimers to approximate to 97 nm for v1/v2 dimers. The minimal binding region supporting these interactions lies between amino acids 97-278, which are shared by nearly all Hax-1 proteins, indicating that additional factors regulate the preferential formation of Hax-1 homo- or heterodimers. Our studies are the first to show that Hax-1 is a family of anti- and proapoptotic regulators that may modulate cell survival and death through homo- or heterodimerization.