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Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

M Steklov1,2, S Pandolfi1,2, M F Baietti1,2

  • 1VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium.

Science (New York, N.Y.)
|November 17, 2018
PubMed

Insights

Leucine zipper-like transcriptional regulator 1 (LZTR1) protein regulates RAS signaling by mediating ubiquitination. Loss of LZTR1 function causes Noonan syndrome and affects Schwann cell proliferation, explaining its role in human disease.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • The leucine zipper-like transcriptional regulator 1 (LZTR1) protein is an adaptor for the cullin 3 (CUL3) ubiquitin ligase complex.
  • LZTR1's precise mechanism of action and its role in human diseases remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism of LZTR1 function.
  • To investigate the link between LZTR1, RAS signaling, and human diseases like Noonan syndrome.

Main Methods:

  • Trapping LZTR1 complexes from mammalian cells.
  • Ubiquitome analysis to identify protein ubiquitination changes.
  • Analysis of disease-associated LZTR1 mutations.

Main Results:

  • LZTR1 acts as an adaptor for the CUL3 ubiquitin ligase complex, targeting the guanosine triphosphatase RAS.
  • LZTR1-mediated ubiquitination of RAS at lysine-170 inhibits RAS signaling by reducing membrane association.
  • Loss of Lztr1 in mice recapitulates Noonan syndrome phenotypes and affects Schwann cell behavior.
  • Identified disease-associated LZTR1 mutations impair complex formation or RAS interaction.

Conclusions:

  • LZTR1-mediated ubiquitination of RAS is a key regulatory mechanism.
  • Dysregulation of this pathway explains LZTR1's involvement in human diseases, including Noonan syndrome.

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