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The role of p62/SQSTM1 in sporadic inclusion body myositis.

Authors
  • Nakano, Satoshi1
  • Oki, Mitsuaki2
  • Kusaka, Hirofumi2
  • 1 Department of Neurology, Osaka City General Hospital, Japan. Electronic address: [email protected] , (Japan)
  • 2 Department of Neurology, Kansai Medical University, Japan. , (Japan)
Type
Published Article
Journal
Neuromuscular disorders : NMD
Publication Date
Apr 01, 2017
Volume
27
Issue
4
Pages
363–369
Identifiers
DOI: 10.1016/j.nmd.2016.12.009
PMID: 28159418
Source
Medline
Keywords
License
Unknown

Abstract

We examined selective autophagy against ubiquitinated protein aggregates in sporadic inclusion body myositis (s-IBM) patients. The form of autophagy requires phosphorylation of serine 403 in p62/SQSTM1 to bind to Lys63-linked ubiquitin and the binding of the p62-ubiquitinated protein conjugates to LC3. In muscle biopsy specimens from 16 s-IBM patients, we compared the distribution of p62 (aa120-440) with 1) Ser403-phosphorylated p62 (S403-pp62), 2) Lys63-linked ubiquitin and 3) LC3 in double-colour immunofluorescence microscopy. S403-pp62, Lys63-linked ubiquitin and LC3 colocalised with p62 aggregates, 79.05% ± 13.64% (mean ± SD), 66.54% ± 19.91% and 51.84% ± 14.1%, respectively. Although positive deposits of S403-pp62 and Lys63-linked ubiquitin were always observed within p62 aggregates, LC3 often showed dissociated distribution from p62. We also found fibres containing small, numerous p62-positive dots that were negative for all three markers and were also observed in myositis controls. The results indicate that p62, Lys63-linked ubiquitin and LC3 in s-IBM join to perform selective autophagy. p62 could be induced by some cellular stresses in all types of myositis; however, in s-IBM, compromised binding of the p62-ubiquitinated protein complex to LC3 could stop the autophagy process in its initial stages, which causes the formation of aggregates of p62-oligomers with Lys63-ubiquitinated proteins.

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