Characterization of the anti-type I interferon effects of the cellular flice-like inhibitory protein (CFLIP)

Gates-Tanzer, Lauren Taylor

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https://hdl.handle.net/2142/101696 Copy

Description

Title

Characterization of the anti-type I interferon effects of the cellular flice-like inhibitory protein (CFLIP)

Author(s)

Gates-Tanzer, Lauren Taylor

Issue Date

2018-07-11

Director of Research (if dissertation) or Advisor (if thesis)

Shisler, Joanna

Doctoral Committee Chair(s)

Shisler, Joanna

Committee Member(s)

• Blanke, Steven
• Vanderpool, Cari
• Wilson, Brenda

Department of Study

Microbiology

Discipline

Microbiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• cFLIP
• interferon, innate
• immunity

Abstract

The cellular FLICE-like inhibitory protein (cFLIP) is well known as a major immunomodulatory protein. Various works have described its role in major cellular pathways such as apoptosis, autophagy, necroptosis, NF-KB regulation and more recently, modulation of interferon responses. Interferon alpha (IFNa) and interferon beta (IFNb) are in the class of type I IFN and are critical as the first line of defense against viral infection. Interestingly, these IFNs also maintain roles apart from viral infection including participating in the pathophysiology of tumor biology and autoimmunity. Previous studies found that cFLIPL could inhibit IFNb production. My work demonstrated that this was by inhibiting the major transcription factor for IFNb expression, interferon regulatory factor 3 (IRF3). Mutational analysis revealed that the CLD within the C-terminus of cFLIPL is responsible for inhibiting IRF3-CBP-DNA interactions. Further, when cFLIPL was knocked down in various tumor cell lines, levels of tumor protective interferon stimulated genes (ISGs) increased, suggesting cFLIPL may contribute to tumorigenesis by way of inhibiting IRF3. In addition, cFLIPL also inhibited IFNa production by inhibiting the transcription factor, IRF7. In this case, the CLD of cFLIPL was dispensable to inhibit IFNa production; an alternative shorter isoform, cFLIPS, which lacks the CLD, also inhibited IRF7-induced IFNa expression. IRF7 phosphorylation was greatly reduced in cells expressing cFLIPL and cFLIPS. I hypothesized cFLIP targeted the IKK kinase. In support of this hypothesis, I found that cFLIPL co-IPs with IKa and IKKa-IRF7 interactions were disrupted in the presence of cFLIPL. These interactions were confirmed in a pDC-like cell line overexpressing cFLIP, suggesting that the mechanism by which cFLIP inhibits IFN production is physiologically relevant. Taken together, these data suggest that cFLIP is a major regulator of type I IFNs. It is of major clinical interest to regard the regulation of type I IFN expression by cFLIP when considering the pathophysiology behind diseases like cancer and autoimmunity.

Graduation Semester

2018-08

Type of Resource

text

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http://hdl.handle.net/2142/101696

Copyright and License Information

Copyright 2018 Lauren Taylor Gates-Tanzer

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