MDM2 Mediates Nonproteolytic Polyubiquitylation of the DEAD-Box RNA Helicase DDX24
MDM2 Mediates Nonproteolytic Polyubiquitylation of the DEAD-Box RNA Helicase DDX24
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DOI：
10.1128/mcb.00320-14
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发表时间：
2014-06
影响因子：
5.3
通讯作者：
Takayoshi Yamauchi;Masaaki Nishiyama;T. Moroishi;Kanae Yumimoto;K. Nakayama
中科院分区：
文献类型：
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作者：
Takayoshi Yamauchi;Masaaki Nishiyama;T. Moroishi;Kanae Yumimoto;K. Nakayama
MDM 2介导泛素化，从而触发肿瘤抑制蛋白p53的蛋白酶体降解。然而，遗传学证据表明，MDM 2有助于独立于p53降解的多个调控网络。我们现在已经确定了死亡盒RNA解旋酶DDX 24作为一种核仁蛋白，与MDM 2相互作用。发现DDX 24与MDM 2的中心区域结合，导致DDX 24在体外和体内的多泛素化。然而，出乎意料的是，DDX 24的多泛素化并没有引起其蛋白酶体降解，而是促进了其与前核糖体核糖核蛋白（pre-rRNP）加工复合物的结合，这是前rRNA加工的早期步骤所需的。与这些发现一致，细胞中DDX 24的消耗损害了前rRNA加工，并导致MDM 2功能的消除和随后的p53稳定。因此，我们的研究结果表明，MDM 2在DDX 24的非蛋白水解泛素化中发挥了意想不到的作用，这可能有助于调节前rRNA加工。
ABSTRACT MDM2 mediates the ubiquitylation and thereby triggers the proteasomal degradation of the tumor suppressor protein p53. However, genetic evidence suggests that MDM2 contributes to multiple regulatory networks independently of p53 degradation. We have now identified the DEAD-box RNA helicase DDX24 as a nucleolar protein that interacts with MDM2. DDX24 was found to bind to the central region of MDM2, resulting in the polyubiquitylation of DDX24 both in vitro and in vivo. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing. Consistently with these findings, depletion of DDX24 in cells impaired pre-rRNA processing and resulted both in abrogation of MDM2 function and in consequent p53 stabilization. Our results thus suggest an unexpected role of MDM2 in the nonproteolytic ubiquitylation of DDX24, which may contribute to the regulation of pre-rRNA processing.