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  Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection

Riley, B. E., Kaiser, S. E., Shaler, T. A., Ng, A. C., Hara, T., Hipp, M. S., et al. (2010). Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol, 191(3), 537-52. doi:10.1083/jcb.201005012.

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 Creators:
Riley, B. E.1, Author
Kaiser, S. E.1, Author
Shaler, T. A.1, Author
Ng, A. C.1, Author              
Hara, T.1, Author              
Hipp, M. S.2, Author              
Lage, K.2, Author              
Xavier, R. J.1, Author
Ryu, K. Y.1, Author
Taguchi, K.1, Author
Yamamoto, M.1, Author
Tanaka, K.1, Author              
Mizushima, N.1, Author
Komatsu, M.1, Author
Kopito, R. R.1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: Animals Autophagy Cells, Cultured Mice Mice, Mutant Strains Microtubule-Associated Proteins/deficiency/genetics/metabolism NF-E2-Related Factor 2/*metabolism Protein Binding Stress, Physiological/*physiology Substrate Specificity Ubiquitin/*metabolism
 Abstract: Genetic ablation of autophagy in mice leads to liver and brain degeneration accompanied by the appearance of ubiquitin (Ub) inclusions, which has been considered to support the hypothesis that ubiquitination serves as a cis-acting signal for selective autophagy. We show that tissue-specific disruption of the essential autophagy genes Atg5 and Atg7 leads to the accumulation of all detectable Ub-Ub topologies, arguing against the hypothesis that any particular Ub linkage serves as a specific autophagy signal. The increase in Ub conjugates in Atg7(-/-) liver and brain is completely suppressed by simultaneous knockout of either p62 or Nrf2. We exploit a novel assay for selective autophagy in cell culture, which shows that inactivation of Atg5 leads to the selective accumulation of aggregation-prone proteins, and this does not correlate with an increase in substrate ubiquitination. We propose that protein oligomerization drives autophagic substrate selection and that the accumulation of poly-Ub chains in autophagy-deficient circumstances is an indirect consequence of activation of Nrf2-dependent stress response pathways.

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 Dates: 2010
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: Other: 21041446
DOI: 10.1083/jcb.201005012
ISSN: 1540-8140 (Electronic)0021-9525 (Linking)
URI: http://www.ncbi.nlm.nih.gov/pubmed/21041446
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Title: J Cell Biol
Source Genre: Journal
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Pages: - Volume / Issue: 191 (3) Sequence Number: - Start / End Page: 537 - 52 Identifier: -