Garg, Abhishek
(2014)
FEEDBACK INHIBITION OF IL-17 RECEPTOR SIGNAL TRANSDUCTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
IL-17 is a proinflammatory cytokine that mediates host defense against extracellular pathogens but also contributes to the pathogenesis of various autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis. Despite some homology with the toll-like receptors, IL-17 receptor subunits (IL-17RA and IL-17RC) do not recruit adaptors such as MyD88, but instead associate with and signal through the E3 ubiquitin ligase Act1. Upon recruitment, Act1 ubiquitinates tumor necrosis factor receptor associated factor 6 (TRAF6), resulting in the activation of downstream transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), CCAAT-enhancer binding proteins (C/EBPs) and mitogen-activated protein kinases (MAPKs). Despite advances in our understanding IL-17 signaling, the details of molecular events involved in negative regulation of IL-17 signaling still remain unclear. Therefore, we focused our attention on feedback inhibitory mechanisms mediated by proteins that are regulated by IL-17. Here we describe three novel inhibitors of IL-17 signal transduction, A20, anaphase promoting complex subunit 5 (AnapC5) and monocyte chemotactic protein 1 induced protein 1 (MCPIP1). We uncovered non-overlapping function of these proteins in IL-17 pathway, signifying their importance in inhibiting inflammatory signaling. A20 is a deubiquitinating enzyme that restricts IL-17-induced TRAF6 ubiquitination, whereas AnapC5 associates with A20 and appears to function as an adaptor protein in the A20/IL-17 pathway. MCPIP1, on the other hand, is an RNase that degrades Il17ra and Il17rc mRNA, thereby restraining IL-17 signaling. Notably, gene expression of A20 and MCPIP1 is regulated by IL-17, indicating feedback inhibition of IL-17 signaling pathway. In summary, our findings have advanced the understanding of IL-17 signaling inhibition, may provide a novel mechanistic approach for controlling IL-17-induced inflammation and ultimately treating IL-17 mediated autoimmune diseases.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 April 2014 |
| Date Type: |
Publication |
| Defense Date: |
10 April 2014 |
| Approval Date: |
25 April 2014 |
| Submission Date: |
23 April 2014 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
182 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
IL-17, IL-17 Signaling, A20, MCPIP1, Deubiquitination |
| Date Deposited: |
25 Apr 2014 13:38 |
| Last Modified: |
15 Nov 2016 14:19 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/21435 |
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