Xue Lei, Igaki Tatsushi, Kuranaga Erina, Kanda Hiroshi, Miura Masayuki, Xu Tian
Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT 06536, USA.
Dev Cell. 2007 Sep;13(3):446-54. doi: 10.1016/j.devcel.2007.07.012.
CYLD encodes a tumor suppressor that is mutated in familial cylindromatosis. Despite biochemical and cell culture studies, the physiological functions of CYLD in animal development and tumorigenesis remain poorly understood. To address these questions, we generated Drosophila CYLD (dCYLD) mutant and transgenic flies expressing wild-type and mutant dCYLD proteins. Here we show that dCYLD is essential for JNK-dependent oxidative stress resistance and normal lifespan. Furthermore, dCYLD regulates TNF-induced JNK activation and cell death through dTRAF2, which acts downstream of the TNF receptor Wengen and upstream of the JNKK kinase dTAK1. We show that dCYLD encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. These data provide a molecular mechanism for the tumor suppressor function of this evolutionary conserved molecule by indicating that dCYLD plays a critical role in modulating TNF-JNK-mediated cell death.
CYLD编码一种在家族性圆柱瘤病中发生突变的肿瘤抑制因子。尽管有生物化学和细胞培养方面的研究，但CYLD在动物发育和肿瘤发生中的生理功能仍知之甚少。为了解决这些问题，我们构建了果蝇CYLD（dCYLD）突变体以及表达野生型和突变型dCYLD蛋白的转基因果蝇。在此我们表明，dCYLD对于JNK依赖的氧化应激抗性和正常寿命至关重要。此外，dCYLD通过dTRAF2调节TNF诱导的JNK激活和细胞死亡，dTRAF2在TNF受体Wengen的下游以及JNKK激酶dTAK1的上游发挥作用。我们发现dCYLD编码一种去泛素化酶，该酶使dTRAF2去泛素化并防止dTRAF2被泛素介导的蛋白水解降解。这些数据通过表明dCYLD在调节TNF-JNK介导的细胞死亡中起关键作用，为这种进化保守分子的肿瘤抑制功能提供了一种分子机制。
