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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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http://pubman.mpdl.mpg.de/cone/persons/resource/persons62350

Ng,  A. C.
Land Surface Dynamics, Research Group Biospheric Theory and Modelling, Dr. A. Kleidon, Max Planck Institute for Biogeochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons60313

Hara,  T.
Quantum Many Body Systems, Max Planck Institute of Quantum Optics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78111

Hipp,  M. S.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98790

Lage,  K.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons37352

Tanaka,  K.
The Atmosphere in the Earth System, MPI for Meteorology, Max Planck Society;
Global Vegetation Modelling, The Land in the Earth System, MPI for Meteorology, Max Planck Society;
IMPRS on Earth System Modelling, MPI for Meteorology, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-4767-D
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.