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

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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

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dc.contributor.author Riley, Brigit E.
dc.contributor.author Kaiser, Stephen E.
dc.contributor.author Shaler, Thomas A.
dc.contributor.author Hara, Taichi
dc.contributor.author Hipp, Mark S.
dc.contributor.author Lage, Kasper
dc.contributor.author Ryu, Kwon-Yul
dc.contributor.author Taguchi, Keiko
dc.contributor.author Yamamoto, Masayuki
dc.contributor.author Tanaka, Keiji
dc.contributor.author Mizushima, Noboru
dc.contributor.author Komatsu, Masaaki
dc.contributor.author Ng, Aylwin Chun-Yeen
dc.contributor.author Xavier, Ramnik
dc.contributor.author Kopito, Ron R.
dc.date.accessioned 2012-03-01T01:19:34Z
dc.date.issued 2010
dc.identifier.citation Riley, Brigit E., Stephen E. Kaiser, Thomas A. Shaler, Aylwin C.Y. Ng, Taichi Hara, Mark S. Hipp, Kasper Lage, 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. Journal of Cell Biology 191(3): 537-552. en_US
dc.identifier.issn 0021-9525 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8296044
dc.description.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. en_US
dc.language.iso en_US en_US
dc.publisher Rockefeller University Press en_US
dc.relation.isversionof doi:10.1083/jcb.201005012 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003313/pdf/ en_US
dash.license LAA
dc.title 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 en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Journal of Cell Biology en_US
dash.depositing.author Xavier, Ramnik
dc.date.available 2012-03-01T01:19:34Z
dash.affiliation.other HMS^Medicine-Massachusetts General Hospital en_US

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