Human Molecular Genetics Advance Access published online on November 1, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm320
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases.
1 Neurodegeneration Research Lab, National Neuroscience Institute, Singapore. 2 Institute for Cell Engineering, Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3 Departments of Neurology, Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4 Neuroscience, Physiology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 5 Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. 7 Duke-NUS Graduate Medical School, National University of Singapore, Singapore. 8 Department of Biological Sciences, National University of Singapore, Singapore.
* To whom all correspondence should be addressed: Kah-Leong Lim, Ph.D. Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Tel: (65)-6357-7520 Fax: (65)-6256-9178 E-mail: Kah_Leong_Lim{at}nni.com.sg
Received September 19, 2007; Revised October 29, 2007; Accepted October 29, 2007
Although ubiquitin-enriched protein inclusions represent an almost invariant feature of neurodegenerative diseases, the mechanism underlying their biogenesis remains unclear. In particular, whether the topology of ubiquitin linkages influences the dynamics of inclusions is not well explored. Here we report that lysine 48 (K48) and lysine 63 (K63)-linked polyubiquitination, as well as monoubiquitin modification contribute to the biogenesis of inclusions. K63-linked polyubiquitin is the most consistent enhancer of inclusions formation. Under basal conditions, ectopic expression of K63 mutant ubiquitin in cultured cells promotes the accumulation of proteins and the formation of intracellular inclusions in the apparent absence of proteasome impairment. When co-expressed with disease-associated tau and SOD1 mutants, K63 ubiquitin mutant facilitates the formation of tau- and SOD-1-positive inclusions. Moreover, K63-linked ubiquitination was found to selectively facilitate the clearance of inclusions via autophagy. These data indicate that K63-linked ubiquitin chains may represent a common denominator underlying inclusions biogenesis, as well as a general cellular strategy for defining cargo destined for the autophagic system. Collectively, our results provide a novel mechanistic route that underlies the life cycle of an inclusion body. Harnessing this pathway may offer innovative approaches in the treatment of neurodegenerative disorders.
# Authors contributed equally
9 Current address: Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. T. Zheng, S. Shahnazari, A. Brech, T. Lamark, T. Johansen, and J. H. Brumell The Adaptor Protein p62/SQSTM1 Targets Invading Bacteria to the Autophagy Pathway J. Immunol., November 1, 2009; 183(9): 5909 - 5916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Ju, S. E. Miller, P. I. Hanson, and C. C. Weihl Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease J. Biol. Chem., October 31, 2008; 283(44): 30289 - 30299. [Abstract] [Full Text] [PDF]
|
|