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

Neurobiol Aging. 2011 Dec;32(12):2323.e27-40. doi: 10.1016/j.neurobiolaging.2010.06.010. Epub 2010 Jul 31.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Nucleus / genetics*
  • Cell Nucleus / pathology
  • Cells, Cultured
  • Cytoplasmic Granules / genetics
  • Cytoplasmic Granules / pathology
  • HEK293 Cells
  • Humans
  • Inclusion Bodies / genetics
  • Mice
  • Molecular Sequence Data
  • Motor Neurons / physiology
  • Mutation / genetics*
  • Nuclear Localization Signals / genetics*
  • Oxidative Stress / genetics*
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism


  • Nuclear Localization Signals
  • RNA-Binding Protein FUS