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FUNCTIONAL REGULATION OF INTERLEUKIN-17 RECEPTOR SIGNALING

Cruz, J. Agustin (2018) FUNCTIONAL REGULATION OF INTERLEUKIN-17 RECEPTOR SIGNALING. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

An appropriate inflammatory immune response requires the effective orchestration of molecular and cellular effectors. Interleukin-17 (IL-17) is a cytokine, small signaling proteins, made by immune cells to communicate with mainly non-immune cells. IL-17 signaling engages its receptor (IL-17R) to induce inflammation by stabilizing transcripts or by inducing expression of target genes. IL-17R downstream intermediate proteins activate and downregulate intracellular signaling. IL-17R shares some, but not all, intracellular intermediate proteins with Toll-like receptor (TLR) and Tumor necrosis factor α receptor (TNFR) signaling. Previous research has shown that not all intermediates from TLR or TNFR1 pathways participate of IL-17R signaling. We aimed to identify novel intermediate proteins acting downstream in IL-17R by using molecular and cellular biology and biochemical techniques. After identifying five possible novel intermediates that either activate (caveolin-1 and AnapC3) or inhibit (ABIN-1, CYLD, Otulin) IL-17R signaling, we aimed to describe the mechanism of action of two of them, ABIN-1 and caveolin-1. We described the molecular mechanisms by which ubiquitin-binding protein ABIN-1 and membrane-bound scaffolding protein Caveolin-1 control IL-17 signaling. Interestingly, as previous research on other signaling intermediates of IL-17R signaling has shown, IL-17R signaling also regulates the expression of these two proteins in what we propose is a self-modulatory signaling mechanism. Specifically, we identified that ABIN-1 inhibits baseline and IL-17-activated signaling by binding polyubiquitin independently of A20. Moreover, we showed that IL-17 signaling induced degradation of ABIN-1. For caveolin-1, we observed a different mechanism of regulation. Thus, Caveolin-1 interacted with a subunit of IL-17R and regulated trafficking of IL-17R to the cell surface. Interestingly, caveolin-1 regulatory functions correlated with an activating role of caveolin-1 in IL-17R signaling. Lastly, caveolin-1 was downregulated by IL-17 signaling. In this thesis we report novel functions for ABIN-1 and caveolin-1 downstream of IL-17R. These results provide insight into the mechanism by which ABIN-1 and caveolin-1 regulate IL-17R signaling, and how IL-17R signaling self-regulates by modulating the expression or degradation of these two proteins. The results from this thesis contribute to the understanding of IL-17-mediated inflammatory signaling, and set the groundwork for future research on therapies to modulate this inflammatory response.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cruz, J. Agustincucho@pitt.educucho0000-0002-4927-9140
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGaffen, Sarahsarah.gaffen@pitt.edusig65
Committee MemberGalbiati, Ferrucciofeg5@pitt.edufeg5
Committee MemberBomberger, Jenniferjbomb@pitt.edujbomb
Committee MemberSarkar, Saumendrasaumen@pitt.edusaumen
Committee MemberKane, Lawrencelkane@pitt.edulkane
Date: 26 January 2018
Date Type: Publication
Defense Date: 14 December 2017
Approval Date: 26 January 2018
Submission Date: 26 January 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 181
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Interleukin-17, IL-17 receptor, IL-17R signaling, NF-KB signaling, ABIN-1, Caveolin-1, inhibition, activation, molecular biology, cytokine signaling, immunology, CYLD, Otulin, ubiquitin
Date Deposited: 26 Jan 2018 15:44
Last Modified: 26 Jan 2018 15:44
URI: http://d-scholarship.pitt.edu/id/eprint/33734

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