Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway

• Published in: The Journal of biological chemistry Vol. 289; no. 36; pp. 24944 - 24955
• Main Authors: Kageyama, Shun, Sou, Yu-shin, Uemura, Takefumi, Kametaka, Satoshi, Saito, Tetsuya, Ishimura, Ryosuke, Kouno, Tsuguka, Bedford, Lynn, Mayer, R. John, Lee, Myung-Shik, Yamamoto, Masayuki, Waguri, Satoshi, Tanaka, Keiji, Komatsu, Masaaki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.09.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autophagy; Cell Biology; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Immunoblotting; Kelch-Like ECH-Associated Protein 1; Liver - metabolism; Liver - pathology; Liver - ultrastructure; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Microscopy, Immunoelectron; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Phagosomes - genetics; Phagosomes - metabolism; Phosphorylation; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Sequestosome-1 Protein; Signal Transduction; Time Factors; Ubiquitin - metabolism; Autophagy-related Protein 7 (ATG7); Protein Aggregation; Autophagy; Nuclear Factor 2 (Erythroid-derived 2-Like Factor) (NFE2L2) (Nrf2); Proteasome
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.580357

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.