Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States.
Institute for Molecular Biology of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Elife. 2022 Apr 25;11:e76495. doi: 10.7554/eLife.76495.
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of . Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1.
RAS GTPases 是高度保守的蛋白，参与调节有丝分裂信号。我们之前描述了一种新型的 Cullin 3 RING E3 泛素连接酶复合物，由底物衔接蛋白 LZTR1 形成，该复合物能够结合、泛素化和促进 RAS GTPase RIT1 的蛋白酶体降解。此外，其他人还描述了该复合物也负责经典 RAS GTPases 的泛素化。在这里，我们分析了果蝇和小鼠中缺失功能突变体的表型，并证明了它们对 RIT1 同源物具有生化偏好。此外，我们表明 在小鼠中是杂合充足的，并且纯合缺失等位基因的胚胎致死性可以通过 删除 来挽救。总体而言，我们的结果表明，在模式生物中，RIT1 同源物是 LZTR1 的首选底物。
