Apoptotic signalling by p53 occurs at both transcriptional and non-transcriptional levels, as p53 may act as a direct apoptogenic stimulus via activation of the intrinsic mitochondrial pathway. HOPS is a highly conserved, ubiquitously expressed shuttling protein with an ubiquitin-like domain. We generated Hops-/- mice and observed that they are viable with no apparent phenotypic defects. However, when treated with chemotherapeutic agents, Hops-/- mice display a significant reduction in apoptosis, suggesting an impaired ability to respond to genotoxic stressors. We show that HOPS acts as a regulator of cytoplasmic p53 levels and function. By binding p53, HOPS inhibits p53 proteasomal degradation and favours p53 recruitment to mitochondria and apoptosis induction. By interfering with importin α, HOPS further increases p53 cytoplasmic levels. Thus, HOPS promotes the p53-dependent mitochondrial apoptosis pathway by preserving cytoplasmic p53 from both degradation and nuclear uptake.

中文翻译：

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HOPS/TMUB1 将 p53 保留在细胞质中并维持 p53 依赖性线粒体凋亡。


p53 的细胞凋亡信号发生在转录和非转录水平上，因为 p53 可能通过激活内在线粒体途径充当直接的细胞凋亡刺激物。 HOPS 是一种高度保守、普遍表达的穿梭蛋白，具有类似泛素的结构域。我们培育了 Hops-/- 小鼠，并观察到它们能够存活，没有明显的表型缺陷。然而，当用化疗药物治疗时，Hops-/-小鼠的细胞凋亡显着减少，表明其对基因毒性应激源的反应能力受损。我们证明 HOPS 作为细胞质 p​​53 水平和功能的调节剂。通过结合 p53，HOPS 抑制 p53 蛋白酶体降解，并有利于 p53 募集到线粒体和诱导细胞凋亡。通过干扰输入蛋白 α，HOPS 进一步增加 p53 细胞质水平。因此，HOPS 通过保护细胞质 p​​53 免受降解和核摄取来促进 p53 依赖性线粒体凋亡途径。