Identification and Characterization of Moesin-, PIP2-mediated Solid Particle Phagocytosis
Date
2018-08-09
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Abstract
Phagocytosis is the defining feature of professional phagocytes of the innate immune system. This function is typically carried out by phagocytic receptors on the cell surface. These receptors can mediate binding and engulfment of solid particles. However, these phagocytic receptors have evolved very recently in history comparing to phagocytosis as a conserved cellular function. This suggests a primordial form of phagocytosis might exist. Years ago, our laboratory uncovered an expected phagocytic mechanism that solid particle can bind to membrane lipids on phagocytes to trigger lipid sorting. Consequently, this can lead to phagocytosis akin to FcγR-based phagocytosis regarding its dependence on Immunoreceptor Tyrosine-based Activation Motif (ITAM), Src-family kinases, Syk, and phosphoinositide 3-kinase (PI3K). Based on these findings, we proposed a hypothetical mechanism for solid particle phagocytosis termed “Signaling Equivalent Platform” (SEP). In short, membrane engagement with solid structures, either via ligand/receptor binding or merely being stabilized by an approaching solid surface will lead to a shared downstream pathway with the same dependence on ITAM and Syk. Both modes of phagocytosis are equivalent for its activation by solid structures. However, the identity of the ITAM-containing molecule and the exact involvement of lipid during solid particle phagocytosis under SEP is still unclear. This thesis serves to strengthen the idea of SEP by identifying the ITAM-containing molecule and further characterizing the involvement of the ITAM-containing molecule and lipids during solid particle phagocytosis. We used a generic ITAM sequence as a probe and identified moesin as the ITAM-containing molecule from the mouse genome. We further demonstrated that a solid structure binding to the cell surface leads to autonomous accumulation of phosphatidylinositol 4, 5-bisphosphate (PIP2) to the site of contact, which attracts moesin, a conserved structural linker, to the plasma membrane. Moreover, Moesin, via its ITAM, is sufficient to activate phagocytic programming including Syk and downstream signaling that is virtually identical to that initiated by Fcγ receptors. Bioinformatic analysis suggested that this moesin-mediated signaling predates modern Fcγ and immune receptors. This thesis, therefore, reveals an evolutionarily conserved moesin-, PIP2-mediated signaling platform for the evolutionarily conserved phagocytosis that provides essential components for modern ITAM-based signaling cascades.
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Keywords
Phagocytosis, Moesin, Solid Particle Phagocytosis, Phosphatidylinositol-4,5-bisphosphate
Citation
Tu. Z. (2018). Identification and Characterization of Moesin-, PIP2-mediated Solid Particle Phagocytosis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32804