Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

M. Steklov; S. Pandolfi; M. F. Baietti; A. Batiuk; P. Carai; P. Najm; M. Zhang; H. Jang; F. Renzi; Y. Cai; L. Abbasi Asbagh; T. Pastor; M. De Troyer; M. Simicek; E. Radaelli; H. Brems; E. Legius; J. Tavernier; K. Gevaert; F. Impens; L. Messiaen; R. Nussinov; S. Heymans; S. Eyckerman; A. A. Sablina

doi:10.1126/science.aap7607

Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

M. Steklov, S. Pandolfi, M. F. Baietti, A. Batiuk, P. Carai, P. Najm, M. Zhang, H. Jang, F. Renzi, Y. Cai, L. Abbasi Asbagh, T. Pastor, M. De Troyer, M. Simicek, E. Radaelli, H. Brems, E. Legius, J. Tavernier, K. Gevaert, F. ImpensL. Messiaen, R. Nussinov, S. Heymans, S. Eyckerman, A. A. Sablina^*

^*Corresponding author for this work

Human Molecular Genetics Biochemistry

Research output: Contribution to journal › Article › peer-review

128 Scopus citations

Abstract

The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

Original language	English
Pages (from-to)	1177-1182
Number of pages	6
Journal	Science
Volume	362
Issue number	6419
DOIs	https://doi.org/10.1126/science.aap7607
State	Published - 7 Dec 2018

Funding

Funders	Funder number
National Cancer Institute	ZIABC010440
National Cancer Institute
H2020 European Research Council
Fonds Wetenschappelijk Onderzoek

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Abbasi Asbagh, L., Pastor, T., De Troyer, M., Simicek, M., Radaelli, E., Brems, H., Legius, E., Tavernier, J., Gevaert, K., ... Sablina, A. A. (2018). Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science, 362(6419), 1177-1182. https://doi.org/10.1126/science.aap7607

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title = "Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination",

abstract = "The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.",

author = "M. Steklov and S. Pandolfi and Baietti, {M. F.} and A. Batiuk and P. Carai and P. Najm and M. Zhang and H. Jang and F. Renzi and Y. Cai and {Abbasi Asbagh}, L. and T. Pastor and {De Troyer}, M. and M. Simicek and E. Radaelli and H. Brems and E. Legius and J. Tavernier and K. Gevaert and F. Impens and L. Messiaen and R. Nussinov and S. Heymans and S. Eyckerman and Sablina, {A. A.}",

year = "2018",

month = dec,

day = "7",

doi = "10.1126/science.aap7607",

language = "אנגלית",

volume = "362",

pages = "1177--1182",

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Steklov, M, Pandolfi, S, Baietti, MF, Batiuk, A, Carai, P, Najm, P, Zhang, M, Jang, H, Renzi, F, Cai, Y, Abbasi Asbagh, L, Pastor, T, De Troyer, M, Simicek, M, Radaelli, E, Brems, H, Legius, E, Tavernier, J, Gevaert, K, Impens, F, Messiaen, L, Nussinov, R, Heymans, S, Eyckerman, S & Sablina, AA 2018, 'Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination', Science, vol. 362, no. 6419, pp. 1177-1182. https://doi.org/10.1126/science.aap7607

TY - JOUR

T1 - Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

AU - Steklov, M.

AU - Pandolfi, S.

AU - Baietti, M. F.

AU - Batiuk, A.

AU - Carai, P.

AU - Najm, P.

AU - Zhang, M.

AU - Jang, H.

AU - Renzi, F.

AU - Cai, Y.

AU - Abbasi Asbagh, L.

AU - Pastor, T.

AU - De Troyer, M.

AU - Simicek, M.

AU - Radaelli, E.

AU - Brems, H.

AU - Legius, E.

AU - Tavernier, J.

AU - Gevaert, K.

AU - Impens, F.

AU - Messiaen, L.

AU - Nussinov, R.

AU - Heymans, S.

AU - Eyckerman, S.

AU - Sablina, A. A.

PY - 2018/12/7

Y1 - 2018/12/7

N2 - The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

AB - The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

UR - http://www.scopus.com/inward/record.url?scp=85056800408&partnerID=8YFLogxK

U2 - 10.1126/science.aap7607

DO - 10.1126/science.aap7607

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AN - SCOPUS:85056800408

SN - 0036-8075

VL - 362

SP - 1177

EP - 1182

JO - Science

JF - Science

IS - 6419

ER -

Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

Abstract

Funding

UN SDGs

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