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

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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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Mole Rats
Proteasome Endopeptidase Complex
Proteins
HSP40 Heat-Shock Proteins
HSP72 Heat-Shock Proteins
Atomic Force Microscopy
Cytosol
Proteolysis
Gel Chromatography
Mass Spectrometry
Homeostasis
Peptide Hydrolases
Yeasts
Liver

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition. / Rodriguez, Karl A; Osmulski, Pawel; Pierce, Anson; Weintraub, Susan E; Gaczynska, Maria E; Buffenstein, Rochelle.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 11, 01.11.2014, p. 2060-2072.

Research output: Contribution to journalArticle

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