Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

M. Steklov; S. Pandolf; 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. Eyekerman; A. A. Sablina

doi:10.1126/science.aap7607

Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

M. Steklov, S. Pandolf, 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. Eyekerman, A. A. Sablina^*

^*Corresponding author for this work

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

89 Citations (Web of Science)

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 Lztrl 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 Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-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
Publication status	Published - 7 Dec 2018

Keywords

FAST INTERACTION REFINEMENT
RARE VARIANTS
MEMBRANE
FIREDOCK
REVEALS
CHARMM

Access to Document

10.1126/science.aap7607

Cite this

Steklov, M., Pandolf, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., 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

@article{d179d850c8a7438781ea4d2d5bdb3ffa,

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 Lztrl 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 Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-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.",

keywords = "FAST INTERACTION REFINEMENT, RARE VARIANTS, MEMBRANE, FIREDOCK, REVEALS, CHARMM",

author = "M. Steklov and S. Pandolf 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 Asbagh, {L. Abbasi} 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. Eyekerman and Sablina, {A. A.}",

year = "2018",

month = dec,

day = "7",

doi = "10.1126/science.aap7607",

language = "English",

volume = "362",

pages = "1177--1182",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6419",

}

Steklov, M, Pandolf, S, Baietti, MF, Batiuk, A, Carai, P, Najm, P, Zhang, M, Jang, H, Renzi, F, Cai, Y, Asbagh, LA, 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, Eyekerman, 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 - Pandolf, 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 - Asbagh, L. Abbasi

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 - Eyekerman, 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 Lztrl 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 Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-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 Lztrl 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 Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-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.

KW - FAST INTERACTION REFINEMENT

KW - RARE VARIANTS

KW - MEMBRANE

KW - FIREDOCK

KW - REVEALS

KW - CHARMM

U2 - 10.1126/science.aap7607

DO - 10.1126/science.aap7607

M3 - Article

VL - 362

SP - 1177

EP - 1182

JO - Science

JF - Science

SN - 0036-8075

IS - 6419

ER -