This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Salomons, F. A.
Right arrow Articles by Dantuma, N. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Salomons, F. A.
Right arrow Articles by Dantuma, N. P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2009, p. 1774-1785, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01485-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Selective Accumulation of Aggregation-Prone Proteasome Substrates in Response to Proteotoxic Stress{triangledown} ,{dagger}

Florian A. Salomons,1,{ddagger} Victoria Menéndez-Benito,1,{ddagger},§ Claudia Böttcher,1 Brett A. McCray,2,3 J. Paul Taylor,2,3 and Nico P. Dantuma1*

Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Von Eulers Väg 3, S-17177, Stockholm, Sweden,1 Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,2 Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee3

Received 23 September 2008/ Returned for modification 15 October 2008/ Accepted 10 January 2009

Conditions causing an increase in misfolded or aberrant proteins can impair the activity of the ubiquitin/proteasome system (UPS). This observation is of particular interest, given the fact that proteotoxic stress is closely associated with a large variety of disorders. Although impairment of the UPS appears to be a general consequence of proteotoxic insults, the underlying mechanisms remain enigmatic. Here, we show that heat shock-induced proteotoxic stress resulted in conjugation of ubiquitin to detergent-insoluble protein aggregates, which coincided with reduced levels of free ubiquitin and impediment of ubiquitin-dependent proteasomal degradation. Interestingly, whereas soluble proteasome substrates returned to normal levels after a transient accumulation, the levels of an aggregation-prone substrate remained high even when the free ubiquitin levels were restored. Consistently, overexpression of ubiquitin prevented accumulation of soluble but not aggregation-prone substrates in thermally stressed cells. Notably, cells were also unable to resume degradation of aggregation-prone substrates after treatment with the translation inhibitor puromycin, indicating that selective accumulation of aggregation-prone proteins is a consistent feature of proteotoxic stress. Our data suggest that the failure of the UPS to clear aggregated proteins in the aftermath of proteotoxic stress episodes may contribute to the selective deposition of aggregation-prone proteins in conformational diseases.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, The Medical Nobel Institute, Karolinska Institutet, Von Eulers väg 3, S-17177, Stockholm, Sweden. Phone: (46) 8-52487384. Fax: (46) 8-313529. E-mail: nico.dantuma{at}ki.se

{triangledown} Published ahead of print on 21 January 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} F.A.S. and V.M.-B. contributed equally.

§ Present address: Division of Cell Biology II, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Molecular and Cellular Biology, April 2009, p. 1774-1785, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01485-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dantuma, N. P., Lindsten, K. (2009). Stressing the ubiquitin/proteasome system. Cardiovasc Res 0: cvp255v2-cvp255 [Abstract] [Full Text]  
  • Shabek, N., Herman-Bachinsky, Y., Ciechanover, A. (2009). Ubiquitin degradation with its substrate, or as a monomer in a ubiquitination-independent mode, provides clues to proteasome regulation. Proc. Natl. Acad. Sci. USA 106: 11907-11912 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»