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XIAP-p47 Pairing Activates the Immune Deficiency Pathway in the Lyme Disease Tick Ixodes scapularis
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | XIAP-p47 Pairing Activates the Immune Deficiency Pathway in the Lyme Disease Tick Ixodes scapularis. |
| 개인저자 | McClure Carroll, Erin E. |
| 단체저자명 | University of Maryland, Baltimore. Molecular Microbiology and Immunology. |
| 발행사항 | [S.l.]: University of Maryland, Baltimore., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 96 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-02B. Dissertation Abstract International |
| ISBN | 9781085571968 |
| 학위논문주기 | Thesis (Ph.D.)--University of Maryland, Baltimore, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Advisor: Pedra, Joao. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Globally, vector-borne diseases account for 17% of all infectious diseases. Most vectors are blood-feeding arthropods, which transmit bacterial, viral, and parasitic diseases to humans and animals. The tick Ixodes scapularis transmits seven pathogens, including Borrelia burgdorferi, the agent of Lyme disease. Lyme disease is the most important vector-borne disease in the United States and causes an estimated 329,000 infections annually. Best described in the model organism Drosophila melanogaster, the arthropod immune deficiency (IMD) pathway responds to microbial infection through activation of Relish, a nuclear factor (NF)-觀B family transcription factor.In I. scapularis ticks, the E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) regulates the IMD pathway through ubiquitylation. Yet, the tick genome notably lacks homologs to genes encoding key IMD pathway proteins as described in Drosophila. How XIAP activates the IMD pathway in response to microbial infection is poorly characterized and targets of XIAP-mediated ubiquitylation remain unknown. In this study, we identified the XIAP enzymatic substrate p47 as a positive regulator of the I. scapularis IMD network. XIAP polyubiquitylates p47 in a lysine (K)63-dependent manner and interacts with the ubiquitin-like (UBX) domain of p47. p47 also binds to Kenny (IKK款/NF-觀B essential modulator [NEMO]), the regulatory subunit of the inhibitor of NF-觀B kinase (IKK) complex. Replacement of the amino acid lysine with arginine in the p47 linker region completely abrogated molecular interactions with Kenny. Furthermore, reduction of p47 transcription levels through RNA interference in I. scapularis limited Kenny accumulation, reduced phosphorylation of IKK棺 (IRD5), and impaired cleavage of the NF-觀B molecule Relish. Accordingly, disruption of p47 expression increased microbial colonization of the tick-transmitted spirochete B. burgdorferi and the rickettsial agent Anaplasma phagocytophilum. In summary, we demonstrated that XIAP ubiquitylates p47 in a K63-dependent manner, culminating in Relish activation and antimicrobial responses. Manipulating immune signaling cascades in I. scapularis may lead to innovative approaches to reducing the burden of tick-borne diseases. |
| 일반주제명 | Immunology. Biochemistry. Microbiology. Physiology. Public health. Epidemiology. |
| 언어 | 영어 |
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