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Physiological and pathological activation of IKK and IKK-related kinases [electronic resource] / by Xuefeng Wu.

Author
Wu, Xuefeng, 1977-
Published
[University Park, Pa.] : Pennsylvania State University, 2008.
Physical Description
1 electronic document (152 pages)
Additional Creators
Sun, Shao-Cong and Christensen, Neil D.
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Graduate Program
Summary
Owing to its wide range of important biological roles, nuclear factor kappa B (NF-κB) has been intensely investigated for the past two decades. Inactive NF-κB is located in the cytosol complexed with the inhibitory IκB proteins, and its nuclear translocation is induced through phosphorylation-mediated degrdation of IκB, a molecular event that in turn is mediated by IκB kinase (IKK). NF-κB activation is generally a transient process due to its tight regulation by negative feedbacks, thus timely inducing targeted genes involved in diverse biological processes. Defect in NF-κB negative regulations, due to either genetic deficiencies or pathological actions, can lead to severe diseases, such as inflammation and cancer. Thus, deciphering the negative regulation of NF-κB represents a highly significant and challenging area of NF-κB research. The primary goal of this thesis research project is to better understand the molecular mechanisms mediating the abnormal NF-κB activation. Specifically, two aspects of abnormal NF-κB activation were focused on. One was the pathological activation of NF-κB by retroviral oncoprotein Tax encoded by the human T-cell leukemia virus type I (HTLV-I). The other aspect was the genetic deficiency of a negative regulator, cyclindromatosis (CYLD). In Chapter II, I described one novel mechanism by which Tax mediates constitutive NF-κB and IKK activation. HTLV-I Tax oncoprotein persistently activates NF-κB, which is required for HTLV-I-mediated T-cell transformation. NF-κB activation by Tax has been shown through its capacity of stimulating the activity of IκB kinase (IKK), but the underlying mechanism remained elusive. We showed here that Tax functions as an intracellular stimulator of an IKK-activating kinase, Tak1. Additionally, Tax physically interacts with Tak1 and mediates the recruitment of IKK to Tak1. In HTLV-I-infected T cells, Tak1 is constitutively activated and complexed with both Tax and IKK. We provided genetic evidence that Tak1 is essential for Tax-induced IKK activation. Interestingly, ubiquitin-binding function of IKKγ, which is essential for cellular stimuli induced NF-κB activation, is not required for Tax-specific NF-κB signaling. These findings demonstrate a pathological mechanism of IKK activation by Tax and provide an example for how IKK is persistently activated in cancer cells. The focus of Chapter III is CYLD, a deubiquitination enzyme that regulates the ubiquitination and signaling function of key components involved in activation of NF-κB. By employing CYLD knockout mice, we discovered a novel function of CYLD in the regulation of antiviral responses. CYLD deficiency causes constitutive activation of the atypical IκB kinases, IKKε and TBK1, and aberrant induction of type I interferons (IFN-Is) in virus-infected cells. CYLD acts by preventing basal ubiquitination and signaling function of an IKKε/TBK1 activator, RIG-I. Interestingly, despite their competence in IFN production, the CYLD-deficient cells and mice are considerably more susceptible to viral infection. We provided genetic evidence that IFN-induced signaling and antiviral gene expression are attenuated in the absence of CYLD. These findings suggest that CYLD mediates effective and controlled antiviral responses by preventing IKKε/TBK1 deregulation and modulating IFN receptor signaling. Since IKKε/TBK1 deregulation is associated with oncogenesis, these findings also have implications on the tumor suppressor function of CYLD. Based on that CYLD negatively regulates IKKε/TBK1, Chapter IV is dedicated to investigate the crosstalk between IKKε/TBK1 and CYLD by focusing on mechanism of CYLD phosphorylation. Previously, we observed that CYLD undergoes transient phosphorylation at an IKKγ (NEMO)-dependent manner. In this chapter, I described the identification of a critical serine site, Ser418 of CYLD as an inducible phosphorylation site using mass spectrometry analysis and a phospho-specific α-CYLD antibody. Mutation of serine 418 to alanine renders CYLD superactive, since expression of the CYLD S418A mutant blocks the activation of IKK and JNK by mitogens and TNFα. Thus, CYLD phosphorylation appears to serve as a mechanism that temporally inactivates its DUB function. Furthermore, genetic evidence was provided that IKKε/TBK1 mediate phosphorylation of CYLD. Finally, given that the physiological functions of CYLD phosphorylation have not been explored, I highlighted future directions to elucidating mechanism by which CYLD, as a tumor suppressor, encounters IKKε/TBK1 in the oncogenesis process in Chapter V. Taken together, investigation on the crosstalk between CYLD and IKKε/TBK1 may provide further insights into development of novel strategies for cancer prevention and treatment.
Other Subject(s)
Dissertation Note
Ph.D. Pennsylvania State University 2008.
Note
Mode of access: World Wide Web.
Thesis advisor: Shao-Cong Sun, Neil Christensen.
Reproduction Note
Microfilm (positive). 1 reel 35 mm. (University Microfilms 34-14388.
Technical Details
The full text of the dissertation is available as a Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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