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首页> 外文期刊>Cell cycle >Int6 and Moe1 interact with Cdc48 to regulate ERAD and proper chromosome segregation.
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Int6 and Moe1 interact with Cdc48 to regulate ERAD and proper chromosome segregation.

机译：Int6和Moe1与Cdc48相互作用以调节ERAD和适当的染色体分离。

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Int6/eIF3e is implicated in tumorigenesis, but its molecular functions remain unclear. We have studied its fission yeast homolog Yin6, reporting that it regulates proteolysis by controlling the assembly/localization of proteasomes, and binds directly to another conserved protein, Moe1. In the present study, we isolated Cdc48 as a Moe1-binding protein from a yeast two-hybrid screen, and confirmed biochemically that they form a stable complex in fission yeast. Overexpressing Moe1 or Yin6 partially rescued phenotypes of cdc48 mutants; conversely, overexpressing Cdc48 partially rescued phenotypes of moe1 or yin6 mutants. Mutants defective in both Cdc48 and the Yin6-Moe1 complex showed growth defects that were far more severe than either alone. These double mutants were severely deficient in endoplasmic reticulum associated degradation (ERAD), as they were hypersensitive to accumulation of misfolded proteins. In addition, their chromosomes showed frequent defects in spindle attachment and segregation--these mitotic defects correlated with Ase1 and Bir1/survivin mislocalization. These results suggest that Cdc48, Yin6 and Moe1 act in the same protein complex to concertedly control ERAD and chromosome segregation. Many of these properties are evolutionarily conserved in humans, since human Cdc48 rescued the lethality of the yeast cdc48Delta mutant, and Int6 and Moe1/eIF3d bind Cdc48 in human cells.
机译：Int6 / eIF3e与肿瘤发生有关，但其分子功能仍不清楚。我们已经研究了它的裂变酵母同系物Yin6，报告说它通过控制蛋白酶体的组装/定位来调节蛋白水解，并直接与另一个保守的蛋白Moe1结合。在本研究中，我们从酵母双杂交筛选中分离出作为Moe1结合蛋白的Cdc48，并在生物化学上证实它们在裂变酵母中形成了稳定的复合物。过表达Moe1或Yin6可部分拯救cdc48突变体的表型。相反，过表达Cdc48可以部分挽救moe1或yin6突变体的表型。在Cdc48和Yin6-Moe1复合体中都具有缺陷的突变体显示出生长缺陷，其严重程度远高于任何一个。这些双突变体严重缺乏内质网相关降解（ERAD），因为它们对错误折叠的蛋白质积累非常敏感。此外，它们的染色体在纺锤体附着和分离中经常出现缺陷-这些有丝分裂缺陷与Ase1和Bir1 / survivin错位有关。这些结果表明，Cdc48，Yin6和Moe1在同一蛋白复合物中起作用，以一致地控制ERAD和染色体分离。由于人类Cdc48挽救了酵母cdc48Delta突变体的致死性，并且Int6和Moe1 / eIF3d结合了人类细胞中的Cdc48，因此许多这些特性在人类中都是进化保守的。

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