Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs
- University of California, San Francisco, United States
- Consejo Superior de Investigaciones Científicas, Spain
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Spain
- University of California, Davis, United States
- New York University, United States
Abstract
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 Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all Figures.
Article and author information
Author details
Joaquim Grego-Bessa
Funding
National Cancer Institute (F31CA265066)
- Antonio Cuevas-Navarro
National Cancer Institute (R35CA197709)
- Frank McCormick
National Cancer Institute (R00CA245122)
- Pau Castel
DOD CDMRP Neurofibromatosis Research Program (W81XWH-20-1-0391)
- Pau Castel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN165444 and #AN179937) of the University of California San Francisco.
Copyright
© 2022, Cuevas-Navarro et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs
eLife 11:e76495.
https://doi.org/10.7554/eLife.76495
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