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

doi:10.1016/j.bbadis.2014.07.005

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

Biochim Biophys Acta. 2014 Nov;1842(11):2060-72. doi: 10.1016/j.bbadis.2014.07.005. Epub 2014 Jul 10.

Authors

Karl A Rodriguez¹, Pawel A Osmulski², Anson Pierce³, Susan T Weintraub⁴, Maria Gaczynska², Rochelle Buffenstein⁵

Affiliations

¹ Sam and Ann Barshop Institute for Aging and Longevity Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr., San Antonio, TX 78245, USA; Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
² Sam and Ann Barshop Institute for Aging and Longevity Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr., San Antonio, TX 78245, USA; Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr., San Antonio, TX 78245, USA.
³ Mitchell Center for Neurodegenerative Diseases, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
⁴ Department of Biochemistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
⁵ Sam and Ann Barshop Institute for Aging and Longevity Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr., San Antonio, TX 78245, USA; Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: [email protected].

Abstract

The naked mole-rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~31years) 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.

Keywords: Aging; Heat shock protein; Naked mole-rat; Protease inhibitor; Proteasome; Protein degradation.

Abstract

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