A common theme that is emerging from studies of neurodegenerative disorders is the involvement of misfolded proteins and defects in the ubiquitin-proteasome system. The ubiquitin-proteasome system was originally considered to be the machinery for tagging and destroying unwanted proteins. However, recent evidence indicates that the ubiquitin-proteasome system is also involved in protein unfolding, intracellular Iprotein targeting, cell signaling and transcription. Our laboratory identified ubiquilin, the founding member of an exciting new class of proteins, which appears to inhibit degradation of proteins. Ubiquilin contains multiple ubiquitin-related motifs typically found in proteins involved in the ubiquitin-proteasome system. We identified ubiquilin through its interactions with presenilin proteins, mutations in which are associated with early-onset familia_ Alzheimer's Disease. Overexpression of ubiquilin in cells increases presenilin protein levels, decreases levels of endoproteolytic N- and C-terminal presenilin fragments, and decreases ubiquitination of presenilin proteins. Several lines of evidence, including results from our laboratory, suggest that ubiquilin expression is induced during cell stress and that it may function as a molecular chaperone, a ubiquitin-receptor, or in cell survival. We propose to use a multi-pronged approach to determine the role ubiquilin proteins play in cells and organisms. Using cellular, molecular, and immunological techniques, we will determine the expression patterns of the different ubiquilin proteins in tissues and tissue culture cells as well as the intracellular localization properties of different ubiquilin isotypes. We will determine how different domains of the ubiquilin polypeptide are involved in the functions of the protein. We will use both transfection assays, as well as an in vitro celt-free translation assay, to identify the role ubiquilin plays in the ubiquitin-proteasome system. We will characterize ubiquilin-interacting proteins using co-immunoprecipitation and yeast two-hybrid assays. Finally, we propose to use gene knockout in mouse, anti-sense inhibition in C. elegans and human tissue culture cells, and antibody neutralization to identify the effects that loss of ubiquilin have in cells and organisms. The results obtained from the proposed research will lead to a better understanding of the functional role of ubiquilin in cells and in whole organisms, and ultimately, its role in health and in disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SSS-P (01))
Program Officer
Shapiro, Bert I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of MD Biotechnology Institute
Organized Research Units
United States
Zip Code
Ugolino, Janet; Fang, Shengyun; Kubisch, Christian et al. (2011) Mutant Atp13a2 proteins involved in parkinsonism are degraded by ER-associated degradation and sensitize cells to ER-stress induced cell death. Hum Mol Genet 20:3565-77
Zhong, Yongwang; Wang, Yang; Yang, Hui et al. (2011) Importin beta interacts with the endoplasmic reticulum-associated degradation machinery and promotes ubiquitination and degradation of mutant alpha1-antitrypsin. J Biol Chem 286:33921-30
Dong, G; Ferguson, J M; Duling, A J et al. (2011) Modeling pathogenesis of Huntington's disease with inducible neuroprogenitor cells. Cell Mol Neurobiol 31:737-47
Rothenberg, Cara; Srinivasan, Deepa; Mah, Leann et al. (2010) Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet 19:3219-32
Rothenberg, Cara; Monteiro, Mervyn J (2010) Ubiquilin at a crossroads in protein degradation pathways. Autophagy 6:979-80
Yang, Hui; Liu, Chao; Zhong, Yongwang et al. (2010) Huntingtin interacts with the cue domain of gp78 and inhibits gp78 binding to ubiquitin and p97/VCP. PLoS One 5:e8905
Wang, Hongmin; Lim, Precious J; Karbowski, Mariusz et al. (2009) Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18:737-52
Lim, Precious J; Danner, Rebecca; Liang, Jing et al. (2009) Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD. J Cell Biol 187:201-17
Wang, Hongmin; Monteiro, Mervyn J (2007) Ubiquilin overexpression reduces GFP-polyalanine-induced protein aggregates and toxicity. Exp Cell Res 313:2810-20
Ford, Diana L; Monteiro, Mervyn J (2007) Studies of the role of ubiquitination in the interaction of ubiquilin with the loop and carboxyl terminal regions of presenilin-2. Biochemistry 46:8827-37

Showing the most recent 10 out of 17 publications