KRAS regulation by small non-coding RNAs and SNARE proteins

• Published in: Nature communications 2019-11, Vol.10 (1), p.5118-15, Article 5118
• Main Authors: Che, Yonglu, Siprashvili, Zurab, Kovalski, Joanna R., Jiang, Tiffany, Wozniak, Glenn, Elcavage, Lara, Khavari, Paul A.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 14/63; 631/208; 631/67; 82/58; Animals; Cell Line, Tumor; Cell Membrane - metabolism; Disruption; Endocytosis; Endosomes - metabolism; Gene Expression Regulation, Neoplastic; Growth factors; Humanities and Social Sciences; Humans; K-Ras protein; Localization; Mice; multidisciplinary; Neoplasms - metabolism; Neoplasms - pathology; Protein Binding; Protein Transport; Proteins; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; RNA, Small Untranslated - genetics; RNA, Small Untranslated - metabolism; Science; Science (multidisciplinary); Signal Transduction; SNAP receptors; SNARE Proteins - metabolism; Solubilization; Transport; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13106-4

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. Small nucleolar RNAs, SNORD50A/B are frequently deleted in cancers and can inhibit KRAS but by unclear means. Here, the authors show that KRAS trafficking and enrichment on the plasma membrane is mediated by SNARE vesicle transport proteins and that SNORD50A/B compete with these proteins to antagonise these effects.