Nuclear localization sequence of FUS and induction of stress granules by ALS mutants

Jozsef Gal; Jiayu Zhang; David M. Kwinter; Jianjun Zhai; Hongge Jia; Jianhang Jia; Haining Zhu

doi:10.1016/j.neurobiolaging.2010.06.010

Nuclear localization sequence of FUS and induction of stress granules by ALS mutants

Jozsef Gal, Jiayu Zhang, David M. Kwinter, Jianjun Zhai, Hongge Jia, Jianhang Jia, Haining Zhu

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

165 Scopus citations

Abstract

Mutations in fused in sarcoma (FUS) have been reported to cause a subset of familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly localized in the nuclei of neurons, but the ALS mutants are partly mislocalized in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32 amino acid residues of FUS constitute an effective nuclear localization sequence (NLS) as it targeted beta-galactosidase (LacZ, 116 kDa) to the nucleus. Deletion of or the ALS mutations within the NLS caused cytoplasmic mislocalization of FUS. Moreover, we identified the poly-A binding protein (PABP1), a stress granule marker, as an interacting partner of FUS. Large PABP1-positive cytoplasmic foci (i.e. stress granules) colocalized with the mutant FUS inclusions but were absent in wild-type FUS-expressing cells. Processing bodies, which are functionally related to stress granules, were adjacent to but not colocalized with the mutant FUS inclusions. Our results suggest that the ALS mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic inclusions and stress granules, and potentially perturb RNA metabolism.

Original language	English
Pages (from-to)	2323.e27-2323.e40
Journal	Neurobiology of Aging
Volume	32
Issue number	12
DOIs	https://doi.org/10.1016/j.neurobiolaging.2010.06.010
State	Published - Dec 2011

Bibliographical note

Funding Information:
We gratefully thank Dr. Lawrence J. Hayward for wild-type FUS plasmid. We are grateful to Drs. Edward Kasarskis and Qingjun Wang for helpful discussions and reading the manuscript. This work was in part supported by the National Institutes of Health grants R01NS049126 and R21AG032567 to HZ. The support from the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease (COBRE, P20RR020171 ) funded by National Center for Research Resources is acknowledged.

Funding

We gratefully thank Dr. Lawrence J. Hayward for wild-type FUS plasmid. We are grateful to Drs. Edward Kasarskis and Qingjun Wang for helpful discussions and reading the manuscript. This work was in part supported by the National Institutes of Health grants R01NS049126 and R21AG032567 to HZ. The support from the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease (COBRE, P20RR020171 ) funded by National Center for Research Resources is acknowledged.

Funders	Funder number
Corporacion Nacional del Cobre
Center of Biomedical Research Excellence in the Molecular Basis of Human Disease
National Institutes of Health (NIH)	R21AG032567, R01NS049126
National Institute of Neurological Disorders and Stroke	R01NS077284
National Center for Research Resources	P20RR020171

Keywords

ALS
FUS/TLS
Nuclear localization sequence (NLS)
Poly-A binding protein 1 (PABP1)
Processing bodies
RNA metabolism
Stress granules

ASJC Scopus subject areas

General Neuroscience
Aging
Developmental Biology
Clinical Neurology
Geriatrics and Gerontology

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10.1016/j.neurobiolaging.2010.06.010

Cite this

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title = "Nuclear localization sequence of FUS and induction of stress granules by ALS mutants",

abstract = "Mutations in fused in sarcoma (FUS) have been reported to cause a subset of familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly localized in the nuclei of neurons, but the ALS mutants are partly mislocalized in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32 amino acid residues of FUS constitute an effective nuclear localization sequence (NLS) as it targeted beta-galactosidase (LacZ, 116 kDa) to the nucleus. Deletion of or the ALS mutations within the NLS caused cytoplasmic mislocalization of FUS. Moreover, we identified the poly-A binding protein (PABP1), a stress granule marker, as an interacting partner of FUS. Large PABP1-positive cytoplasmic foci (i.e. stress granules) colocalized with the mutant FUS inclusions but were absent in wild-type FUS-expressing cells. Processing bodies, which are functionally related to stress granules, were adjacent to but not colocalized with the mutant FUS inclusions. Our results suggest that the ALS mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic inclusions and stress granules, and potentially perturb RNA metabolism.",

keywords = "ALS, FUS/TLS, Nuclear localization sequence (NLS), Poly-A binding protein 1 (PABP1), Processing bodies, RNA metabolism, Stress granules",

author = "Jozsef Gal and Jiayu Zhang and Kwinter, \{David M.\} and Jianjun Zhai and Hongge Jia and Jianhang Jia and Haining Zhu",

note = "Funding Information: We gratefully thank Dr. Lawrence J. Hayward for wild-type FUS plasmid. We are grateful to Drs. Edward Kasarskis and Qingjun Wang for helpful discussions and reading the manuscript. This work was in part supported by the National Institutes of Health grants R01NS049126 and R21AG032567 to HZ. The support from the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease (COBRE, P20RR020171 ) funded by National Center for Research Resources is acknowledged. ",

year = "2011",

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doi = "10.1016/j.neurobiolaging.2010.06.010",

language = "English",

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AU - Gal, Jozsef

AU - Zhang, Jiayu

AU - Kwinter, David M.

AU - Zhai, Jianjun

AU - Jia, Hongge

AU - Jia, Jianhang

AU - Zhu, Haining

N1 - Funding Information: We gratefully thank Dr. Lawrence J. Hayward for wild-type FUS plasmid. We are grateful to Drs. Edward Kasarskis and Qingjun Wang for helpful discussions and reading the manuscript. This work was in part supported by the National Institutes of Health grants R01NS049126 and R21AG032567 to HZ. The support from the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease (COBRE, P20RR020171 ) funded by National Center for Research Resources is acknowledged.

PY - 2011/12

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N2 - Mutations in fused in sarcoma (FUS) have been reported to cause a subset of familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly localized in the nuclei of neurons, but the ALS mutants are partly mislocalized in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32 amino acid residues of FUS constitute an effective nuclear localization sequence (NLS) as it targeted beta-galactosidase (LacZ, 116 kDa) to the nucleus. Deletion of or the ALS mutations within the NLS caused cytoplasmic mislocalization of FUS. Moreover, we identified the poly-A binding protein (PABP1), a stress granule marker, as an interacting partner of FUS. Large PABP1-positive cytoplasmic foci (i.e. stress granules) colocalized with the mutant FUS inclusions but were absent in wild-type FUS-expressing cells. Processing bodies, which are functionally related to stress granules, were adjacent to but not colocalized with the mutant FUS inclusions. Our results suggest that the ALS mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic inclusions and stress granules, and potentially perturb RNA metabolism.

AB - Mutations in fused in sarcoma (FUS) have been reported to cause a subset of familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly localized in the nuclei of neurons, but the ALS mutants are partly mislocalized in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32 amino acid residues of FUS constitute an effective nuclear localization sequence (NLS) as it targeted beta-galactosidase (LacZ, 116 kDa) to the nucleus. Deletion of or the ALS mutations within the NLS caused cytoplasmic mislocalization of FUS. Moreover, we identified the poly-A binding protein (PABP1), a stress granule marker, as an interacting partner of FUS. Large PABP1-positive cytoplasmic foci (i.e. stress granules) colocalized with the mutant FUS inclusions but were absent in wild-type FUS-expressing cells. Processing bodies, which are functionally related to stress granules, were adjacent to but not colocalized with the mutant FUS inclusions. Our results suggest that the ALS mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic inclusions and stress granules, and potentially perturb RNA metabolism.

KW - ALS

KW - FUS/TLS

KW - Nuclear localization sequence (NLS)

KW - Poly-A binding protein 1 (PABP1)

KW - Processing bodies

KW - RNA metabolism

KW - Stress granules

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SN - 0197-4580

VL - 32

SP - 2323.e27-2323.e40

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 12

ER -

Nuclear localization sequence of FUS and induction of stress granules by ALS mutants

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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