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Loss-of-function of ubiquitin ligase adaptor LZTR1 triggers human disease by dysregulating RAS ubiquitination

ABSTRACT: Mutations in LZTR1, a substrate adaptor for cullin 3 (CUL3) ubiquitin ligase complexes, have been recently associated with Noonan syndrome and familial Schwannomatosis. Concordantly, we found that Lztr1+/- mice showed craniofacial abnormalities, cardio defects, and premature ageing; whereas loss of LZTR1 in Schwann cells drives their dedifferentiation into proliferating, pro-myelinating cells. In the present dataset we screened for changes in the ubiquitin landscape induced by LZTR1 loss of function by mass spectrometry-based proteomics and identified RAS proteins as substrates of the LZTR1/CUL3 complex. In follow-up experiments we showed that LZTR1/CUL3 inhibits the RAS pathway by ubiquitinating RAS at K170 and triggering its dissociation from the membrane. Disease-associated LZTR1 mutations affect either the LZTR1/CUL3 complex formation, or the interaction with RAS proteins. Together, our results position LZTR1 as a key node in the RAS pathway, loss-of-function of which leads to human disease.

INSTRUMENT(S): Q Exactive HF, LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Fibroblast, Mef Cell

DISEASE(S): Noonan Syndrome,Neurilemmomatosis

SUBMITTER: Impens Francis

LAB HEAD: Anna A Sablina

PROVIDER: PXD007035 | Pride | 2018-11-07

REPOSITORIES: Pride

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Loss-of-function of ubiquitin ligase adaptor LZTR1 triggers human disease by dysregulating RAS ubiquitination

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