Kim, Man Lyang. IKKÎ± regulation of canonical NF-ÎºB activation downstream of Nod1-mediated peptidoglycan recognition : "and" Endocytosis-independent function of clathrin heavy chain in the control of basal NF-ÎºB activation. 2010, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_9308
In the first part of dissertation, we focus on understanding the previously unknown function of IKKα in the canonical NF-κB pathway, associated with inflammation and innate immunity. We show that silencing of IKKα by RNA interference (RNAi) significantly reduced phosphorylation and degradation of IκBα, and nuclear translocation of NF-κB, and secretion of the pro-inflammatory chemokine interleukin-8 (IL-8) during Shigella flexneri infection of human epithelial HeLa cells. This suggests that IKKα like IKKβ plays a pivotal role in inflammation and innate immunity by mediating NF-κB activation in response to microbial infection.
Proper control of NF-κB activation is essential for inflammation and innate immunity triggered by microbial infection, but the dysregulation of NF-κB is associated with various diseases such as chronic inflammatory diseases and cancers. Thus, the NF-κB pathway has been a target of therapeutic drug development. Although constitutive and excessive NF-κB activation has been detected in many inflammation-related diseases, the cause of the constitutive NF-κB activation in non-stimulated cells is largely unknown.
In the second part of dissertation, we focus on clathrin heavy chain (CHC), a well-known regulator of endocytosis that plays a novel endocytosis-independent function as an inhibitor of basal NF-κB activation. We show that silencing of CHC induced constitutive NF-κB nuclear translocation and high level of IL-8 secretion in resting cells. We revealed that constitutive NF-κB nuclear translocation was mediated through the constant IκBα degradation in an IKKα-dependent mechanism. We further showed that CHC depletion-induced constitutive IκBα degradation and high level of IL-8 secretion in resting cells was independent of the inhibition of clathrin-mediated endocytosis (CME) as silencing of μ2 subunit of AP2 complex (AP2M1), an adaptor protein essential for CME failed to induce the constitutive IκBα degradation and high level of IL-8 secretion. Therefore, the results presented may suggest a potential link between a defect in CHC expression and chronic inflammatory disorders and cancers.
|Advisors:||Cornelis, Guy R.|
|Committee Members:||Dehio, Christoph|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Molecular Microbiology (Cornelis)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||126 S.|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||26 Jan 2011 14:43|
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