자료유형  

 학위논문

Control Number  

0017163071

International Standard Book Number  

9798346567295

Dewey Decimal Classification Number  

616.079

Main Entry-Personal Name  

Landau, Lauren Michelle.

Publication, Distribution, etc. (Imprint  

[S.l.] : Harvard University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

176 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-05, Section: B.

General Note  

Advisor: Kagan, Jonathan.

Dissertation Note  

Thesis (Ph.D.)--Harvard University, 2024.

Summary, Etc.  

요약Innate immune cells within mammalian organisms function as the first line of defense against infectious threats. Phagocytes, such as macrophages, respond to microbial insults by sensing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) and activating downstream signal transduction proteins. These signaling pathways are tightly regulated to trigger various inflammatory responses, which activate the adaptive immune system and promote the resolution of infection or damage. The host interferon response represents one such system that is central to antiviral immunity. The expression of type I interferons is governed by upstream PRRs that nucleate oligomeric supramolecular organizing centers (SMOCs) via adaptor proteins including STING, TRIF, and MAVS. These adaptors utilize a conserved pLxIS motif to activate the downstream kinase TBK1 and transcription factor IRF3.Apart from the established roles of STING, TRIF, and MAVS in IRF3 activation, the existence of additional pathways and functions associated with the pLxIS motif is unknown. Leveraging a synthetic biology-based platform to isolate and dissect pLxIS motif activities, we revealed an unexpected diversity and specificity in signaling mechanisms. This system enabled us to identify two orphan proteins that utilize pLxIS motifs, in conjunction with contiguous motifs in the same domain, to stimulate interferon responses independently of the established pathways. These two proteins, IRSp53 and GMIP, may regulate interferon signaling pathways within fibroblasts. Another interferon adaptor protein, TASL, employs an alternative mechanism whereby its pLxIS motif is physically separated from the requisite kinase activation motif downstream of MyD88. Further mechanistic analysis uncovered variable functions of each pLxIS-containing domain in activating IRF3, the TRAF6 ubiquitin ligase, IκB kinases, mitogen-activated protein kinases, and metabolic activities. This diversification enabled subsets of pLxIS-containing proteins to confer protection against viral infection in human cells. Overall, these collective findings establish pLxIS-containing domains as commonly used and biochemically flexible regulators of interferons and metabolism. They furthermore underscore the value of synthetic biology as a tool to discover additional regulators of innate immunity.

Subject Added Entry-Topical Term  

Immunology.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Virology.

Index Term-Uncontrolled  

Infection

Index Term-Uncontrolled  

Interferon

Index Term-Uncontrolled  

Macrophage

Index Term-Uncontrolled  

Innate immunity

Index Term-Uncontrolled  

STING

Index Term-Uncontrolled  

TRIF

Added Entry-Corporate Name  

Harvard University Medical Sciences

Host Item Entry  

Dissertations Abstracts International. 86-05B.

Electronic Location and Access  

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Control Number  

joongbu:657281