LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases

Abstract

Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a substrate adaptor of E3 ubiquitin ligase complex. Mutations in LZTR1 have been identified in glioblastoma and RASopathies. Here, we demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway. The degradation of RAS was observed in cells expressing HRAS, NRAS, KRAS, MRAS, RIT1, RRAS2 as well as oncogenic RAS mutants and inhibited the activation of ERK1/2 and cell growth. Taken together, these results show that LZTR1 functions as a RAS killer protein.