Sialylation as a mechanism for preferential Ligand binding in CFS1R

<p>Macrophages are immune cells that help provide the first line of defense against a wide range of internal and external insults and create the bridge between innate and adaptive immune responses. When macrophage homeostasis is disrupted, disease states occur. Associated disease states include rheumatoid arthritis, Alzheimer’s disease, and multiple sclerosis. The survival and proliferation of macrophages is largely controlled by signaling through colony stimulating factor 1 receptor (CSF1R). Notably, this receptor can be activated by two non-homologous ligands, colony stimulating factor 1 (CSF1) and interleukin- 34 (IL-34). These two ligands are differentially required for macrophage homeostasis across body systems and have different associated pathologies. The ability to separately influence these ligands could provide a novel therapeutic target for these diseases. While the differential effects of CSF1Rs dual ligands have been demonstrated, the structural mechanisms leading to these effects are not well understood. I have found that IL-34 preferentially activates the smaller glycoprotein 130kD (gp130) version of the CSF1R receptor while CSF1 activates both gp130 and the larger glycoprotein 150kD (gp150) forms of the receptor. This provides a novel explanation for the differential signaling and binding affinity seen between the ligands. Additionally, I have shown that gp130 and gp150 are sialylated with both α2-3 and α2-6 linkages. Interestingly, gp130 also exhibits α2- 8 polysialic acid chains. Polysialylation has been previously associated with immunomodulation, but I have found that treating cells with an enzyme that can remove poly sialic acid potentiates proliferation of cells in a ligand dependent manner. This provides a new mechanism for the differential activation and downstream effects found in CSF1R signaling.</p>

Name thesis:degree_name

Master of Science (MS) in Biology

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Biology

Year

2024

Author dc:creator

• Beaulaurier, Eric J.

• Cell Biology
• Immunotherapy

Statement dc:rights

• Access is available to all users

Repository record dc:identifier

https://dc.ewu.edu/theses/926

OAI identifier oai:identifier

oai:dc.ewu.edu:theses-1923