I?B? is the major inhibitor of NF-?B, a family of transcription factors that control transcription of many inflammation-related genes. On the one hand, wounds and infections would never heal without proper inflammation;on the other hand, inflammation has long been associated with the development of cancer, especially metastasis. Therefore, the control of NF-?B transcriptional function is critical for human health. I?B? is a major inhibitor of NF-?B. Inflammatory stimuli, such as cytokines or infections, can trigger rapid degradation of I?B? via the ubiquitin-proteasome pathway. Consequently, NF-?B is activated to transcribe a spectrum of genes related to inflammatory responses. It has been shown that the SCF?TRCP ubiquitin ligase ubiquitinates I?B? upon stimulation. However, little is known about the post-ubiquitinational events of I?B? proteolysis. Polyubiquitinated I?B? still associates with NF-?B, indicating that ubiquitination of I?B? alone is not sufficient to release the inhibitory functin of I?B?. Therefore, the post-ubiquitinational regulation of I?B? is essential for I?B? turnover and NF-?B activation. Understanding this process could pioneer novel therapies to regulate inflammation. Recent studies in our lab suggest that a valosin-containing protein (VCP) and its cofactor, UFD1L, are involved in post-ubiquitinational regulation of I?B?. In this proposal, we wil dissect the mechanisms by which the VCP protein complex regulates I?B? post-ubiquitination. We will also strive to understand how the VCP complex delivers ubiquitinated I?B? to the 26S proteasome, and how the polyubiquitin receptors and deubiquitin enzyme (DUB) are involved in I?B? turnover and NF-?B activation.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM102529-03
Application #
8708127
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Gaillard, Shawn R
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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