The long-term goal of this study is to understand the biological function of protein modification by the ubiquitin like protein ISG15. In recent years our knowledge of protein ubiquitination (ubiquitylation) has expanded rapidly and as a consequence protein ubiquitylation has been found to play important roles in various aspects of cellular function, including the cell cycle, membrane receptor signal transduction, endocytosis, protein quality control, transcription, and DNA repair. In contrast, little is known about the role of protein modification by ISG15. ISG15 is encoded by an interferon stimulated gene. Its expression is highly upregulated by Type I interferon and by bacterial and viral infections. Since ISG15 is not found in simple eukaryotic organisms, such as yeast and nematodes, it is unlikely to be a house keeping gene. Instead, it should be involved in specialized functions in complex organisms, such as human and mouse. In the past four year funding period, we have identified a group of ISG15 targets, characterized the effect of ISG15 modification on some of these targets, identified the ISG15 E2 and a few of the E3 enzymes, and established ISG15 E1 knockout mice. This proposal for the next two-year funding period will test the hypothesis that protein ISG15 modification plays an important role in modulating cellular function during immune responses. The studies proposed in Specific Aim #1 will identify ISG15 modification sites via high throughput screening of ISGylated proteins. The studies proposed in Specific Aim #3 will characterize ISG15 activating enzyme UBE1L knockout mice to examine molecular mechanisms of the function of protein ISGylation. These proposed studies will address important questions about protein ISGylation and may provide valuable insights into the prevention and therapeutic treatment of human diseases, such as pathogen infections and immune defects.

Public Health Relevance

ISG15 and protein modification by ISG15 are strongly induced upon infections by various viruses and bacteria. Furthermore, they are also increased during cancer development and under other toxic stresses. Therefore, it is important to understand their function in order to target this pathway in the control of related human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM066955-06A2
Application #
7533961
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Jones, Warren
Project Start
2002-12-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$320,586
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Maragno, Ana Leticia; Pironin, Martine; Alcalde, Helene et al. (2011) ISG15 modulates development of the erythroid lineage. PLoS One 6:e26068
Zhang, Dongxian; Zhang, Dong-Er (2011) Interferon-stimulated gene 15 and the protein ISGylation system. J Interferon Cytokine Res 31:119-30
Nakka, Venkata P; Lang, Bradley T; Lenschow, Deborah J et al. (2011) Increased cerebral protein ISGylation after focal ischemia is neuroprotective. J Cereb Blood Flow Metab 31:2375-84
Kawabe, Hiroshi; Neeb, Antje; Dimova, Kalina et al. (2010) Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron 65:358-72
Cong, Xiuli; Yan, Ming; Yin, Xiaoyan et al. (2010) Hematopoietic cells from Ube1L-deficient mice exhibit an impaired proliferation defect under the stress of bone marrow transplantation. Blood Cells Mol Dis 45:103-11
Lai, Caroline; Struckhoff, Jessica J; Schneider, Jana et al. (2009) Mice lacking the ISG15 E1 enzyme UbE1L demonstrate increased susceptibility to both mouse-adapted and non-mouse-adapted influenza B virus infection. J Virol 83:1147-51
Yin, Xiaoyan; Cong, Xiuli; Yan, Ming et al. (2009) Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice. Lung Cancer 63:194-200
Yin, Xiaoyan; Cong, Xiuli; Yan, Ming et al. (2009) Alteration of tumor spectrum by ISGylation in p53-deficient mice. Cancer Biol Ther 8:1167-72
Okumura, Fumihiko; Lenschow, Deborah J; Zhang, Dong-Er (2008) Nitrosylation of ISG15 prevents the disulfide bond-mediated dimerization of ISG15 and contributes to effective ISGylation. J Biol Chem 283:24484-8
Malakhova, Oxana A; Zhang, Dong-Er (2008) ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. J Biol Chem 283:8783-7

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