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Cells use autophagy for bulk degradation, in what is often thought of as a nonspecific process. That perception, however, might not be accurate, according to data from Bj?rk?y et al. (page 603). Some autophagy substrates are polyubiquitinated and appear to be targeted for destruction.' i+ y4 g- ~+ z# j% a
; ]$ K7 A$ s+ B; y( ^; KProtein aggregates, such as those found in Huntington's disease, contain polyubiquitinated proteins, as well as the polyubiquitin-binding protein p62.
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* v' {7 r1 h) g" c1 uThe team found that p62 accumulation into protein aggregates depended on its polyubiquitin binding domain and on a polymerization domain, PB1, which allows large chains of p62 to form. p62 also colocalized with LC3, a protein that binds to the autophagosome membrane. Moreover, inhibition of autophagy blocked p62 degradation.
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In cells expressing a mutant huntingtin protein, aggregates containing p62 and LC3 were even more common than in the HeLa cells initially studied. Reducing the amount of p62 expressed caused a higher proportion of the cells in the population to undergo apoptosis.
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The data suggest that p62 helps identify substrates for autophagy via its polyubiquitin binding domain. Using its PB1 domain p62 forms a shell around the aggregate and somehow facilitates an interaction with LC3, which is likely an early step in targeting to autophagosomes. The work provides a molecular link between recognition of polyubiquitinated protein aggregates and garbage disposal by autophagy, and suggests that cells may use protein aggregation as a protective response.(p62 (green) links to ubiquitinated prote) |
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发表于 2009-3-6 08:56
发表于 2015-6-2 22:05
