1. Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway*
- Author
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Masayuki Yamamoto, Shun Kageyama, Lynn Bedford, R. John Mayer, Keiji Tanaka, Satoshi Kametaka, Tetsuya Saito, Tsuguka Kouno, Satoshi Waguri, Masaaki Komatsu, Takefumi Uemura, Ryosuke Ishimura, Myung-Shik Lee, and Yu-shin Sou
- Subjects
Proteasome Endopeptidase Complex ,Time Factors ,NF-E2-Related Factor 2 ,Mutant ,Immunoblotting ,Mice, Transgenic ,Biology ,Biochemistry ,Ubiquitin ,In vivo ,Phagosomes ,Sequestosome-1 Protein ,Autophagy ,Animals ,Phosphorylation ,Microscopy, Immunoelectron ,Molecular Biology ,Heat-Shock Proteins ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Kelch-Like ECH-Associated Protein 1 ,Microscopy, Confocal ,Signal transducing adaptor protein ,Cell Biology ,Cell biology ,Cytoskeletal Proteins ,Proteostasis ,Proteasome ,Liver ,biology.protein ,Function (biology) ,Signal Transduction - Abstract
The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. These pathways are interdependent, and dysfunction in either pathway causes accumulation of ubiquitin-positive aggregates, a hallmark of human pathological conditions. To elucidate in vivo compensatory action(s) against proteasomal dysfunction, we developed mice with reduced proteasome activity in their livers. The mutant mice exhibited severe liver damage, accompanied by formation of aggregates positive for ubiquitin and p62/Sqstm1, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway. These aggregates were selectively entrapped by autophagosomes, and pathological features of livers with impaired proteasome activity were exacerbated by simultaneous suppression of autophagy. In contrast, concomitant loss of p62/Sqstm1 had no apparent effect on the liver pathology though p62/Sqstm1 was indispensable for the aggregates formation. Furthermore, defective proteasome function led to transcriptional activation of the Nrf2, which served as a physiological adaptation. Our in vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis.
- Published
- 2014