Indiana University-Purdue University Indianapolis (IUPUI) / Sensing, integrating, and relaying signals from the environment through proteins,
metabolites, and lipids to the lung are critical for proper development. Moonlighting
proteins, such as AIMP1, are a unique subset that serves at least two independent
physiological functions. Encoded by gene AIMP1, AIMP1 has two known functions: (1)
C-terminus EMAP II domain of full-length AIMP1 can be secreted out of the cell to
chemoattract myeloid cells; (2) intracellular full-length protein interacts with tRNA
synthetases in protein translation. However, despite the linkage of protein expression
levels of with several lung pathologies such as bronchopulmonary dysplasia (BPD),
effectively targeting the protein encoded by AIMP1 has been a challenge due to poorly
understood mechanisms.
This thesis explores physiological, signaling, and immunological moonlighting
mechanisms of first, the extracellular EMAP II then the intracellular AIMP1.
Experiments utilize both in vitro and in vivo models, including a murine model of BPD
and Cre-mediated exon-deletion knockout. Experimental results provide evidence that in
the BPD model, EMAP II levels are elevated and sustained – first in bronchial epithelial
cells then in macrophages. Mice exposed to sustained and elevated EMAP II protein
levels resemble the BPD phenotype while neutralization partially rescued the phenotype,
implying EMAP II as a potential therapeutic target against BPD. Results from studies
exploring EMAP II’s signaling mechanism identify transient stimulation of JAK-STAT3
phosphorylation, commonly found in inflammation-resolving macrophages. In contrast, it
induces unique transcriptional changes that are reversible both by JAK-STAT inhibitor
and siRNA-mediated knockdown of Stat3.
Studies using AIMP1 knockout mouse reveal a novel function for the intracellular
AIMP1. AIMP1 knockout mice exhibited neonatal lethality with a respiratory distress
phenotype, decreased type I alveolar cell expression, and disorganized bronchial
epithelium, suggesting a role in lung maturation. In vitro experiments suggest that a portion of AIMP1 residing in the cell’s membrane interacts with various
phosphatidylinositols and contributes toward F-actin deposition and assembly.
Data from these experimental studies provide insight into how the various
functions of the promiscuous AIMP1 gene affect lung development. These studies
exemplify not only characterize novel moonlighting mechanisms of AIMP1, but also
highlight the importance of characterizing moonlighting proteins to promote therapeutic
preventions. / 2020-02-21
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/20662 |
| Date | 08 1900 |
| Creators | Lee, Dong Il |
| Contributors | Schwarz, Margaret, Tune, Johnathan, Kaplan, Mark, Basile, David |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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