KRAS regulation by small non-coding RNAs and SNARE proteins
KRAS regulation by small non-coding RNAs and SNARE proteins
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DOI：
10.1038/s41467-019-13106-4
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发表时间：
2019-11-11
影响因子：
16.6
通讯作者：
Khavari, Paul A.
中科院分区：
文献类型：
--
作者：
Che, Yonglu;Siprashvili, Zurab;Khavari, Paul A.
KRAS在质膜（PM）处接收并传递信号，在质膜处其将细胞外生长因子信号传递至下游效应物。最近发现SNORD 50 A/B结合KRAS并通过未知机制抑制其致瘤作用。因此，在SNORD 50 A/B野生型和敲除细胞中进行了KRAS邻近蛋白标记，揭示了SNORD 50 A/B RNA塑造了KRAS邻近蛋白的组成，特别是通过抑制KRAS与SNARE囊泡转运蛋白SNAP 23、SNAP 29和VAMP 3的邻近。为了保持在PM上富集，KRAS经历内吞、溶解和囊泡运输到PM的循环。在这里，我们报告说，SNARE是必不可少的，这个过程的最后一步，与KRAS本地化的PM促进SNARE，但拮抗SNORD 50 A/B。因此，SNORD 50 A/B RNA和特异性SNARE蛋白之间的拮抗作用控制KRAS定位、信号传导和肿瘤发生，并且破坏SNARE使能的KRAS功能代表了KRAS驱动的癌症中的潜在治疗机会。
KRAS receives and relays signals at the plasma membrane (PM) where it transmits extracellular growth factor signals to downstream effectors. SNORD50A/B were recently found to bind KRAS and inhibit its tumorigenic action by unknown mechanisms. KRAS proximity protein labeling was therefore undertaken in SNORD50A/B wild-type and knockout cells, revealing that SNORD50A/B RNAs shape the composition of proteins proximal to KRAS, notably by inhibiting KRAS proximity to the SNARE vesicular transport proteins SNAP23, SNAP29, and VAMP3. To remain enriched on the PM, KRAS undergoes cycles of endocytosis, solubilization, and vesicular transport to the PM. Here we report that SNAREs are essential for the final step of this process, with KRAS localization to the PM facilitated by SNAREs but antagonized by SNORD50A/B. Antagonism between SNORD50A/B RNAs and specific SNARE proteins thus controls KRAS localization, signaling, and tumorigenesis, and disrupting SNARE-enabled KRAS function represents a potential therapeutic opportunity in KRAS-driven cancer.