Nonubiquitous autophagy
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《细胞学杂志》
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.
Protein aggregates, such as those found in Huntington's disease, contain polyubiquitinated proteins, as well as the polyubiquitin-binding protein p62.
The 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.
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.
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)
Protein aggregates, such as those found in Huntington's disease, contain polyubiquitinated proteins, as well as the polyubiquitin-binding protein p62.
The 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.
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.
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)