2015 Fiscal Year Final Research Report
Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway
| Project/Area Number |
26860224
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Niigata University |
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Principal Investigator |
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Keywords | オートファジー / プロテアソーム / ユビキチン / 凝集体 / Sqstm1/p62 / Nrf2 / Keap1 |
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| Outline of Final Research Achievements |
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. To evaluate in vivo compensatory action 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, 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 mutant livers were exacerbated by simultaneous suppression of autophagy. 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.
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| Free Research Field |
分子遺伝学
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