title: Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway.
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.
authors: From the Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan, the Protein Metabolism Project and.
authors: Shun
authors: S
authors: Kageyama
authors: the Protein Metabolism Project and.
authors: Yu-shin
authors: YS
authors: Sou
authors: the Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
authors: Takefumi
authors: T
authors: Uemura
authors: the Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
authors: Satoshi
authors: S
authors: Kametaka
authors: From the Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan, Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Tetsuya
authors: T
authors: Saito
authors: From the Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan, Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Ryosuke
authors: R
authors: Ishimura
authors: the Protein Metabolism Project and.
authors: Tsuguka
authors: T
authors: Kouno
authors: the Laboratory of Intracellular Proteolysis, School of Biomedical Sciences, University of Nottingham, School of Life Sciences, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors: Lynn
authors: L
authors: Bedford
authors: the Laboratory of Intracellular Proteolysis, School of Biomedical Sciences, University of Nottingham, School of Life Sciences, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors: R John
authors: RJ
authors: Mayer
authors: the Department of Medicine, Samsung Medical Center, Gangnam-gu, Seoul 135-710, Korea, and.
authors: Myung-Shik
authors: MS
authors: Lee
authors: the Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan.
authors: Masayuki
authors: M
authors: Yamamoto
authors: the Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
authors: Satoshi
authors: S
authors: Waguri
authors: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Keiji
authors: K
authors: Tanaka
authors: From the Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan, the Protein Metabolism Project and komatsu-ms@med.niigata-u.ac.jp.
authors: Masaaki
authors: M
authors: Komatsu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Autophagy; Autophagy-related Protein 7 (ATG7); Nuclear Factor 2 (Erythroid-derived 2-Like Factor) (NFE2L2) (Nrf2); Proteasome; Protein Aggregation