The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
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DOI：
10.1091/mbc.e18-11-0702
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发表时间：
2019-08-01
影响因子：
3.3
通讯作者：
Bolger, Timothy A.
中科院分区：
文献类型：
--
作者：
Aryanpur, Peyman P.;Renner, David M.;Bolger, Timothy A.
Ded 1是一种在翻译起始中起重要作用的DEAD盒RNA解旋酶。与真核起始因子4F（eIF 4F）复合物结合，促进48 S前起始复合物组装和mRNA 5'非翻译区的起始位点扫描。大多数先前的Ded 1细胞功能研究是在营养丰富的生长过程中在稳态条件下进行的。然而，在这项工作中，我们研究了它在雷帕霉素（TOR）C1抑制靶向过程中的翻译反应中的作用，并确定了Ded 1作为翻译阻遏物的新功能。我们发现，C-末端突变体的DED 1是有缺陷的下调翻译后TORC 1抑制雷帕霉素。此外，在TORC 1抑制后，eIF 4G 1通常从翻译复合物中解离并降解，并且该过程在突变细胞中减弱。Ded 1在该翻译反应中的功能需求的映射表明，Ded 1酶活性和与eIF 4G 1的相互作用是必需的，而同源寡聚化可能是不必要的。我们的结果是一致的模型，其中Ded 1失速翻译，并专门删除eIF 4G 1从翻译preinitiation复合物，从而删除eIF 4G 1从翻译的mRNA池，并导致两种蛋白质的共降解。DED 1直系同源物之间的共同特征表明，这种作用是保守的，可能与肿瘤发生等病理学有关。
Ded1 is a DEAD-box RNA helicase with essential roles in translation initiation. It binds to the eukaryotic initiation factor 4F (eIF4F) complex and promotes 48S preinitiation complex assembly and start-site scanning of 5' untranslated regions of mRNAs. Most prior studies of Ded1 cellular function were conducted in steady-state conditions during nutrient-rich growth. In this work, however, we examine its role in the translational response during target of rapamycin (TOR) C1 inhibition and identify a novel function of Ded1 as a translation repressor. We show that C-terminal mutants of DED1 are defective in down-regulating translation following TORC1 inhibition using rapamycin. Furthermore, following TORC1 inhibition, eIF4G1 normally dissociates from translation complexes and is degraded, and this process is attenuated in mutant cells. Mapping of the functional requirements for Ded1 in this translational response indicates that Ded1 enzymatic activity and interaction with eIF4G1 are required, while homo-oligomerization may be dispensable. Our results are consistent with a model wherein Ded1 stalls translation and specifically removes eIF4G1 from translation preinitiation complexes, thus removing eIF4G1 from the translating mRNA pool and leading to the codegradation of both proteins. Shared features among DED1 orthologues suggest that this role is conserved and may be implicated in pathologies such as oncogenesis.