A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition

Karl A. Rodriguez, Pawel A. Osmulski, Anson Pierce, Susan T. Weintraub, Maria Gaczynska, Rochelle Buffenstein

    Research output: Contribution to journalArticle

    31 Scopus citations

    Abstract

    The naked mole-rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~. 31. years) life span. Here, we report that the highly active proteasome from the naked mole-rat liver resists attenuation by a diverse suite of proteasome-specific small molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked mole-rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity. Gel filtration coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although Heat shock protein 72 kDa (HSP72) and Heat shock protein 40 kDa (Homolog of bacterial DNAJ1) (HSP40(Hdj1)) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked mole-rat and allow it to successfully defy aging.

    Original languageEnglish (US)
    Pages (from-to)2060-2072
    Number of pages13
    JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
    Volume1842
    Issue number11
    DOIs
    StatePublished - Nov 1 2014

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    Keywords

    • Aging
    • Heat shock protein
    • Naked mole-rat
    • Protease inhibitor
    • Proteasome
    • Protein degradation

    ASJC Scopus subject areas

    • Molecular Biology
    • Molecular Medicine

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