Participation of proteasome-ubiquitin protein degradation in autophagy and the activation of AMP-activated protein kinase

Shaoning Jiang, Dae Won Park, Yong Gao, Saranya Ravi, Victor Darley-Usmar, Edward Abraham, Jaroslaw W. Zmijewski

    Research output: Contribution to journalArticlepeer-review

    28 Citations (Scopus)


    Although activation of the AMP-activated protein kinase (AMPK) as well as of ubiquitin/proteasome degradative pathways play an essential role in the preservation of metabolic homeostasis, little is known concerning interactions between protein turnover and AMPK activity. In the present studies, we found that inhibition of the 26S proteasome resulted in rapid activation of AMPK in macrophages, epithelial and endothelial cells. This was associated with increased levels of non-degraded Ub-protein conjugates, in both cytosolic and mitochondrial fractions. Selective inhibitors of ubiquitination or siRNA-dependent knockdown of Ub-ligase E1 diminished AMPK activation in cells treated with MG132, a 26S proteasome inhibitor. In addition to inhibition of AMPK activation by Ub-ligase E1 inhibitors, deficiency in Park2 mitochondria-associated Ub-ligase E3 also reduced AMPK activation upon dissipation of mitochondrial membrane potential (δψm). Accumulation of Ub-proteins was correlated with decreases in cellular bioenergetics, including mitochondria oxidative phosphorylation, and an increase in ROS formation. Antioxidants, such as N-acetyl-L-cysteine or mitochondria-targeted MitoTEMPO, effectively diminished MG132-induced AMPK activation. Glucose-dependent regulation of AMPK or AMPK-mediated autophagy was modulated by alterations in intracellular levels of Ub-protein conjugates. Our results indicate that accumulation of ubiquitinated proteins alter cellular bioenergetics and redox status, leading to AMPK activation.

    Original languageEnglish
    Pages (from-to)1186-1197
    Number of pages12
    JournalCellular Signalling
    Issue number6
    Publication statusPublished - 2015 Jun 1


    • AMP kinase
    • Autophagy
    • Bioenergetics
    • PARK2
    • Proteasome
    • Ubiquitination

    ASJC Scopus subject areas

    • Cell Biology


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