SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations

Magda Liczmanska; Michael H. Tatham; Barbara Mojsa; Ania Eugui-Anta; Alejandro Rojas-Fernandez; Adel F. M. Ibrahim; Ronald T. Hay

doi:10.1016/j.celrep.2023.112960

SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations

Magda Liczmanska, Michael H. Tatham, Barbara Mojsa, Ania Eugui-Anta, Alejandro Rojas-Fernandez, Adel F. M. Ibrahim, Ronald T. Hay (Lead / Corresponding author)

Molecular Cell and Developmental Biology

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Abstract

The small ubiquitin-like modifier (SUMO) protease SENP6 disassembles SUMO chains from cellular substrate proteins. We use a proteomic method to identify putative SENP6 substrates based on increased apparent molecular weight after SENP6 depletion. Proteins of the lamin family of intermediate filaments show substantially increased SUMO modification after SENP6 depletion. This is accompanied by nuclear structural changes remarkably like those associated with laminopathies. Two SUMO attachment sites on lamin A/C are close to sites of mutations in Emery-Driefuss and limb girdle muscular dystrophy. To establish a direct link between lamin SUMOylation and the observed phenotype, we developed proximity-induced SUMO modification (PISM), which fuses a lamin A/C targeting DARPin to a SUMO E3 ligase domain. This directly targets lamin A/C for SUMO conjugation and demonstrates that enhanced lamin SUMO modification recapitulates the altered nuclear structure manifest after SENP6 depletion. This shows SENP6 activity protects the nucleus against hyperSUMOylation-induced laminopathy-like alterations.

Original language	English
Article number	112960
Number of pages	32
Journal	Cell Reports
Volume	42
Issue number	8
Early online date	8 Aug 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.112960
Publication status	Published - 29 Aug 2023

Keywords

CP: Cell biology
CP: Molecular biology
PISM
SENP6
SUMO
lamin
laminopathy
nuclear blebbing
proteomics

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2023.112960Licence: CC BY

Final Published Version Final published version, 14.3 MBLicence: CC BY

Cite this

@article{0d932114235c4365a3a213df44cf8156,

title = "SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations",

abstract = "The small ubiquitin-like modifier (SUMO) protease SENP6 disassembles SUMO chains from cellular substrate proteins. We use a proteomic method to identify putative SENP6 substrates based on increased apparent molecular weight after SENP6 depletion. Proteins of the lamin family of intermediate filaments show substantially increased SUMO modification after SENP6 depletion. This is accompanied by nuclear structural changes remarkably like those associated with laminopathies. Two SUMO attachment sites on lamin A/C are close to sites of mutations in Emery-Driefuss and limb girdle muscular dystrophy. To establish a direct link between lamin SUMOylation and the observed phenotype, we developed proximity-induced SUMO modification (PISM), which fuses a lamin A/C targeting DARPin to a SUMO E3 ligase domain. This directly targets lamin A/C for SUMO conjugation and demonstrates that enhanced lamin SUMO modification recapitulates the altered nuclear structure manifest after SENP6 depletion. This shows SENP6 activity protects the nucleus against hyperSUMOylation-induced laminopathy-like alterations.",

keywords = "CP: Cell biology, CP: Molecular biology, PISM, SENP6, SUMO, lamin, laminopathy, nuclear blebbing, proteomics",

author = "Magda Liczmanska and Tatham, {Michael H.} and Barbara Mojsa and Ania Eugui-Anta and Alejandro Rojas-Fernandez and Ibrahim, {Adel F. M.} and Hay, {Ronald T.}",

note = "Funding Information: This work was supported by an Investigator Award from Wellcome (217196/Z/19/Z) and a program grant from Cancer Research UK (C434/A21747) to R.T.H. M.L. was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement 765445 (UbiCode). A.E.A. was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement 813599 (TRIM-NET). We would like to thank Streyoshi Mitra and Lars Jansen (University of Oxford) for providing the GFP-AID-SENP6 HeLa cells and Ohad Medalia (University of Zurich) for providing lamin-targeting DARPins. Copyright: {\textcopyright} 2023 The Author(s).",

year = "2023",

month = aug,

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doi = "10.1016/j.celrep.2023.112960",

language = "English",

volume = "42",

journal = "Cell Reports",

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T1 - SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations

AU - Liczmanska, Magda

AU - Tatham, Michael H.

AU - Mojsa, Barbara

AU - Eugui-Anta, Ania

AU - Rojas-Fernandez, Alejandro

AU - Ibrahim, Adel F. M.

AU - Hay, Ronald T.

N1 - Funding Information: This work was supported by an Investigator Award from Wellcome (217196/Z/19/Z) and a program grant from Cancer Research UK (C434/A21747) to R.T.H. M.L. was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement 765445 (UbiCode). A.E.A. was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement 813599 (TRIM-NET). We would like to thank Streyoshi Mitra and Lars Jansen (University of Oxford) for providing the GFP-AID-SENP6 HeLa cells and Ohad Medalia (University of Zurich) for providing lamin-targeting DARPins. Copyright: © 2023 The Author(s).

PY - 2023/8/29

Y1 - 2023/8/29

N2 - The small ubiquitin-like modifier (SUMO) protease SENP6 disassembles SUMO chains from cellular substrate proteins. We use a proteomic method to identify putative SENP6 substrates based on increased apparent molecular weight after SENP6 depletion. Proteins of the lamin family of intermediate filaments show substantially increased SUMO modification after SENP6 depletion. This is accompanied by nuclear structural changes remarkably like those associated with laminopathies. Two SUMO attachment sites on lamin A/C are close to sites of mutations in Emery-Driefuss and limb girdle muscular dystrophy. To establish a direct link between lamin SUMOylation and the observed phenotype, we developed proximity-induced SUMO modification (PISM), which fuses a lamin A/C targeting DARPin to a SUMO E3 ligase domain. This directly targets lamin A/C for SUMO conjugation and demonstrates that enhanced lamin SUMO modification recapitulates the altered nuclear structure manifest after SENP6 depletion. This shows SENP6 activity protects the nucleus against hyperSUMOylation-induced laminopathy-like alterations.

AB - The small ubiquitin-like modifier (SUMO) protease SENP6 disassembles SUMO chains from cellular substrate proteins. We use a proteomic method to identify putative SENP6 substrates based on increased apparent molecular weight after SENP6 depletion. Proteins of the lamin family of intermediate filaments show substantially increased SUMO modification after SENP6 depletion. This is accompanied by nuclear structural changes remarkably like those associated with laminopathies. Two SUMO attachment sites on lamin A/C are close to sites of mutations in Emery-Driefuss and limb girdle muscular dystrophy. To establish a direct link between lamin SUMOylation and the observed phenotype, we developed proximity-induced SUMO modification (PISM), which fuses a lamin A/C targeting DARPin to a SUMO E3 ligase domain. This directly targets lamin A/C for SUMO conjugation and demonstrates that enhanced lamin SUMO modification recapitulates the altered nuclear structure manifest after SENP6 depletion. This shows SENP6 activity protects the nucleus against hyperSUMOylation-induced laminopathy-like alterations.

KW - CP: Cell biology

KW - CP: Molecular biology

KW - PISM

KW - SENP6

KW - SUMO

KW - lamin

KW - laminopathy

KW - nuclear blebbing

KW - proteomics

UR - http://www.scopus.com/inward/record.url?scp=85166930666&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112960

DO - 10.1016/j.celrep.2023.112960

M3 - Article

C2 - 37556322

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 112960

ER -

SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Establishing the Basis for Selectivity in the SUMO Spray (Investigator Award)

Harnessing the PML-SUMO-RNF4 Axis for Cancer Therapy (Programme Grant)

Cite this

SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Establishing the Basis for Selectivity in the SUMO Spray (Investigator Award)

Harnessing the PML-SUMO-RNF4 Axis for Cancer Therapy (Programme Grant)

Cite this