The role of membrane trafficking regulation for mast cell-mediated allergic disorders

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Allergies pose a serious and increasing public health problem. Critical effector functions in allergic disease are mediated by mast cells. Upon allergen-induced activation, mast cells rapidly degranulate and release a multitude of inflammatory mediators that orchestrate the allergic reaction. Granule exocytosis during mast cell activation requires a series of highly ordered and tightly regulated membrane trafficking events. Perturbation of any of these vital steps during mast cell degranulation can have severe consequences for mast cell function. Thus, there is intense interest in unraveling the cellular processes that ultimately regulate mast cell degranulation and mediator release, as it may provide novel therapeutic targets for mast cell-mediated allergic disorders. However, despite all efforts, many of the basic molecular and cellular mechanisms that regulate vesicle trafficking during mast cell degranulation are still poorly understood.Our research group intensively studies the role of membrane trafficking processes for immune cell signaling and function. To characterize novel regulatory mechanisms of mast cell degranulation and to investigate their physiological relevance for allergic/anaphylactic reactions, we here propose to study the roles of two distinct regulators of membrane trafficking, Lyst and Rin3, in mast cell biology. Preliminary work by our group already strongly indicates a critical role of these molecules in mast cells. To define the function of Lyst and Rin3 in mast cell-mediated allergic reactions, we will employ a dual strategy, in which cell biological and mechanistic in vitro studies are complemented by analysis of anaphylactic reactions in vivo utilizing Lyst- and Rin3-deficient mice. Major aims of the proposal are the characterization of the role of lysosomal trafficking regulator Lyst for mast cell granule organization/structure and its functional impact on mast cell-mediated allergic/anaphylactic reactions. Moreover, we will also perform a detailed functional and mechanistic analysis of the role of the Rab5-specific guanine nucleotide exchange factor Rin3 for mast cell mediator release and anaphylactic reactions. Together, the proposed experiments on the role of membrane trafficking regulators for mast cell function will not only provide novel insights into the complex regulatory mechanisms of mast cell degranulation, but may also reveal how perturbations in these processes can contribute to the pathophysiology of allergic disease.In addition, financial support of the project will foster a promising young scientist, Andreas Westphal, who is just finishing his PhD studies in Prof. Lees laboratory. Andreas Westphals excellent studies on the role of Lyst in innate immune cells provide the basis for the proposed studies and have earned him a first authorship on our recent publication in the Journal of Experimental Medicine (Westphal et al., JEM, 2016).