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 language | English (US) |
|---|---|
| Pages (from-to) | 2060-2072 |
| Number of pages | 13 |
| Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| Volume | 1842 |
| Issue number | 11 |
| DOIs | |
| State | Published - 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
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 journal › Article
}
TY - JOUR
T1 - A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition
AU - Rodriguez, Karl A
AU - Osmulski, Pawel
AU - Pierce, Anson
AU - Weintraub, Susan E
AU - Gaczynska, Maria E
AU - Buffenstein, Rochelle
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
KW - Aging
KW - Heat shock protein
KW - Naked mole-rat
KW - Protease inhibitor
KW - Proteasome
KW - Protein degradation
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UR - http://www.scopus.com/inward/citedby.url?scp=84907986019&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2014.07.005
DO - 10.1016/j.bbadis.2014.07.005
M3 - Article
VL - 1842
SP - 2060
EP - 2072
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 11
ER -