The role of p62/SQSTM1 in sporadic inclusion body myositis.
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.
Department of Neurology, Osaka City General Hospital, Japan. Electronic address: s-nakano@med.osakacity-hp.or.jp.
Satoshi
S
Nakano
Department of Neurology, Kansai Medical University, Japan.
Mitsuaki
M
Oki
Department of Neurology, Kansai Medical University, Japan.
Hirofumi
H
Kusaka
D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018979:Myositis, Inclusion Body / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
C118585:P62 protein, human; D016601:RNA-Binding Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin
LC3; Lys63-linked ubiquitin; Selective autophagy; Sporadic inclusion body myositis (s-IBM); p62/SQSTM1