Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway

Shun Kageyama, Yu Shin Sou, Takefumi Uemura, Satoshi Kametaka, Tetsuya Saito, Ryosuke Ishimura, Tsuguka Kouno, Lynn Bedford, R. John Mayer, Myung Shik Lee, Masayuki Yamamoto, Satoshi Waguri, Keiji Tanaka, Masaaki Komatsu

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24944-24955
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number36
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway'. Together they form a unique fingerprint.

Cite this