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The role of selective mrna deadenylation in the homeostatic control of innate immune signaling Rachel Marilyn Braun
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Braun, Rachel Marilyn, author.
- Language:
- English
- Subjects (All):
- Biochemistry.
- Molecular biology.
- Immunology.
- Biology.
- Genetics.
- 0487.
- 0307.
- 0982.
- 0306.
- 0369.
- Local Subjects:
- Biochemistry.
- Molecular biology.
- Immunology.
- Biology.
- Genetics.
- 0487.
- 0307.
- 0982.
- 0306.
- 0369.
- Genre:
- Academic theses
- Physical Description:
- 1 online resource (167 pages)
- Contained In:
- Dissertations Abstracts International 87-12B
- Place of Publication:
- Ann Arbor : ProQuest Dissertations and Theses, 2026
- Language Note:
- English
- Summary:
- The homeostatic control of innate immunity is essential to health as dysregulation can lead to poor outcomes during infection or inflammatory conditions including autoimmunity. Interferon signaling is the specific antiviral arm of the innate immune system responsible for inducing interferons and downstream signaling to control viral infection. While much is known about the stimuli-dependent induction of interferons, less is known about the molecular mechanisms responsible for maintaining low basal levels of interferons in the absence of stimulation or the precise mechanisms by which interferons are rapidly returned to baseline post-activation. Through genetic screening, RNA interference and molecular genetics, we identify that the RNA-binding protein, Tristetraprolin, and selective factors of the mRNA deadenylation machinery post-transcriptionally control interferon mRNAs both at steady state and post-stimulation. Loss of these mRNA decay factors leads to increased interferon levels and increased interferon signaling. Mechanistically, we find that interferon mRNAs are sensitive to targeted deadenylation by this machinery, as loss of the mRNA decay factors leads to increased poly(A) tail length in addition to enhanced stability and translation of interferon transcripts. Altogether, this leads to a potent block against viral infection in vitro and in vivo. Moreover, we find that transient induction of interferon signaling by loss of mRNA decay primes cells, inducing a memory-like state characterized by enhanced induction of interferon upon secondary challenge. Functionally, this decay-mediated control of interferon suggests that modulation of interferon decay could serve as an approach to combat infectious diseases or to induce long-term antiviral protection through priming. We find that this post-transcriptional control of interferons is highly specific to tristetraprolin-driven decay and that tristetraprolin is selectively regulated by diverse activators of interferon signaling, including viral infection. Finally, we find that a human variant in tristetraprolin associated with the inflammatory disease, rheumatoid arthritis, impacts decay-mediated regulation of interferon and infection outcomes. Altogether, this dissertation defines a novel mechanism by which interferons are regulated post-transcriptionally and proposes that modulation of tristetraprolin-driven interferon decay could serve as a promising and tunable immunomodulatory therapeutic approach against diverse infectious diseases and autoimmunity
- Notes:
- Source: Dissertations Abstracts International, Volume: 87-12, Section: B.
- Advisors: Cherry, Sara; Liu, Kathy Fange Committee members: Lynch, Kristen W.; Taabazuing, Cornelius Y.; Henao-Mejia, Jorge
- Ph.D. University of Pennsylvania 2026
- Vendor supplied data
- Local Notes:
- School code: 0175
- ISBN:
- 9798247979364
- Access Restriction:
- Restricted for use by site license
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