Pharmacology and Therapeutics - Theses
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ItemExpression and function of the novel membrane-spanning protein, MS4A8B, in the human airways( 2018)The airway epithelium is an important barrier interface that protects the lungs against environmental insults and pathogens. Airway epithelial cells are increasingly recognized as key regulators of lung immune homeostasis by orchestrating various aspects of both innate and adaptive immunity. Dysfunction of airway epithelial cell functions have been strongly associated with the pathogenesis of various airway disorders. In this body of work, I identify the expression of a novel membrane-spanning protein, MS4A8B, on the motile cilia of airway epithelial cells. Predictive protein sequence analysis reveals the presence of an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its intracellular C- terminal domain. MS4A8B is a member of the MS4A protein family, which comprises a group of 4-domain membrane-spanning proteins. Whilst the core functions of MS4A proteins have not been established, they have been suggested to play active roles in cellular signaling, cellular proliferation and differentiation. Examination of MS4A8B expression in the human airways reveals a highly restricted pattern of expression that is induced only upon mucociliary differentiation of airway epithelial cells. MS4A8B protein is localized to the motile cilia of the airway epithelium in human airway biopsies and in differentiated primary bronchial airway epithelial cell (PBEC) cultures. The expression of MS4A8B decreased in various airway inflammatory disorders including asthma and chronic obstructive pulmonary disease (COPD). In vitro assessment of MS4A8B function reveal that it possesses immune-regulatory functions, with the putative ITIM motif predicted to be a primary effector. In vitro phosphorylation studies show that the putative ITIM motif is capable of being tyrosine phosphorylated, with site-directed mutagenesis of a key tyrosine residue contained in the motif significantly impairing this ability. Combined findings suggest that MS4A8B may exert an important ‘braking’ mechanism on proinflammatory cytokine production in airway epithelial cells, with its observed loss in various airway disorders likely resulting in dysregulated expression of proinflammatory cytokines and the exacerbation of disease symptoms.