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

NEUROBIOLOGY OF AGING

卷:32

Article

Gal, Jozsef¹  Zhang, Jiayu¹  Kwinter, David M.¹  Zhai, Jianjun¹  Jia, Hongge²  Jia, Jianhang^1,2  Zhu, Haining¹ 

[1] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA

[2] Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY 40536 USA

关键词: ALS;    FUS/TLS;    nuclear localization sequence (NLS);    poly-A binding protein 1 (PABP1);    stress granules;    processing bodies;    RNA metabolism;   

DOI  :  10.1016/j.neurobiolaging.2010.06.010

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier Inc. All rights reserved.

【 授权许可】

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