Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth.
Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth.
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DOI：
10.1083/jcb.201409056
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发表时间：
2015-03-16
期刊：
影响因子：
--
通讯作者：
Karbstein K
中科院分区：
文献类型：
--
作者：
Ghalei H;Schaub FX;Doherty JR;Noguchi Y;Roush WR;Cleveland JL;Stroupe ME;Karbstein K
细胞生长依赖于Hrr25/ ck1 δ导向的Ltv1磷酸化，这允许其从新生40S核糖体亚基释放并促进亚基成熟。酪蛋白激酶1δ/ε (CK1δ/ε)及其酵母同源物Hrr25对细胞生长至关重要。此外，CK1δ在几种恶性肿瘤中过表达，CK1δ抑制剂在一些临床前动物研究中显示出希望。然而，Hrr25和CK1δ/ε的底物是细胞生长和存活所必需的，目前尚不清楚。我们发现Hrr25对核糖体组装至关重要，它磷酸化组装因子Ltv1，导致其从新生40S亚基释放并允许亚基成熟。Hrr25失活或非磷酸化Ltv1变体的表达阻断了Ltv1在体外和体内的释放，并阻止了进入翻译样质量控制周期。相反，在Hrr25耗尽后，拟磷Ltv1变体恢复了生存能力。最后，人类乳腺癌细胞中Ltv1的敲低会损害CK1δ/ε抑制剂诱导的细胞凋亡，这表明这些抑制剂的抗增殖活性至少部分是由于核糖体组装的破坏。这些发现验证了核糖体组装途径作为抗癌治疗发展的新靶点。
Cell growth relies on Hrr25/CK1δ-directed phosphorylation of Ltv1, which allows its release from nascent 40S ribosomal subunits and promotes subunit maturation. Casein kinase 1δ/ε (CK1δ/ε) and their yeast homologue Hrr25 are essential for cell growth. Further, CK1δ is overexpressed in several malignancies, and CK1δ inhibitors have shown promise in several preclinical animal studies. However, the substrates of Hrr25 and CK1δ/ε that are necessary for cell growth and survival are unknown. We show that Hrr25 is essential for ribosome assembly, where it phosphorylates the assembly factor Ltv1, which causes its release from nascent 40S subunits and allows subunit maturation. Hrr25 inactivation or expression of a nonphosphorylatable Ltv1 variant blocked Ltv1 release in vitro and in vivo, and prevented entry into the translation-like quality control cycle. Conversely, phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion. Finally, Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly. These findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics.
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影响因子：
64.8
作者：
Gavin, AC;Aloy, P;Superti-Furga, G
通讯作者：
Superti-Furga, G
40S 前后期核糖体内的蛋白质-蛋白质相互作用。
影响因子：
3.7
作者：
Campbell MG;Karbstein K
通讯作者：
Karbstein K
影响因子：
--
作者：
Freed EF;Bleichert F;Dutca LM;Baserga SJ
通讯作者：
Baserga SJ
影响因子：
3.3
作者：
Bhandari D;Zhang J;Menon S;Lord C;Chen S;Helm JR;Thorsen K;Corbett KD;Hay JC;Ferro-Novick S
通讯作者：
Ferro-Novick S
影响因子：
6
作者：
Ghoshal, N;Smiley, JF;Kuret, J
通讯作者：
Kuret, J