Yamauchi Takayoshi, Nishiyama Masaaki, Moroishi Toshiro, Yumimoto Kanae, Nakayama Keiichi I
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Fukuoka, and CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Fukuoka, and CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan
Mol Cell Biol. 2014 Sep;34(17):3321-40. doi: 10.1128/MCB.00320-14. Epub 2014 Jun 30.
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.
MDM2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，MDM2独立于p53降解作用于多个调控网络。我们现已鉴定出DEAD盒RNA解旋酶DDX24为一种与MDM2相互作用的核仁蛋白。发现DDX24与MDM2的中央区域结合，导致DDX24在体外和体内均发生多聚泛素化。然而，出乎意料的是，DDX24的多聚泛素化并未引发其蛋白酶体降解，而是促进了它与核糖体前体核糖核蛋白（pre-rRNP）加工复合物的结合，而这些复合物是前体rRNA加工早期步骤所必需的。与这些发现一致，细胞中DDX24的缺失损害了前体rRNA加工，并导致MDM2功能丧失以及随后的p53稳定。因此，我们的结果表明MDM2在DDX24的非蛋白水解性泛素化中具有意想不到的作用，这可能有助于前体rRNA加工的调控。
