TRPM7 at the Crossroads of Tissue Homeostasis and inflammation

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In all organ systems, timely and non-inflammatory clearance of senescent, damaged and dead cells is a crucial checkpoint at the crossroads of tissue homeostasis and inflammation. Through a specialized form of phagocytosis, termed efferocytosis, the tissue-resident phagocytes recognize, engulf and digest cell corpses without the inflammatory and self-destructive activation of the immune system. Efferocytosis of virally infected cell corpses is also a prerequisite to antigen processing and presentation that lies at the heart of anti-viral immunosurveillance. The mechanisms through which the engulfed corpses are digested in the efferophagosome are highly dependent on Ca2+-signaling but underlying ion channel mechanisms have not been studied. Our preliminary data indicates that the ion channel TRPM7 plays a crucial role in the maturation of the efferophagosome and its ultimate fusion with the lysosomes. Pursuing these tantalizing leads has now laid a strong scientific foundation to hypothesize that: Efferophagosome maturation is controlled by the fusion of M7Vs to the efferophagosome and through TRPM7 channel activity in the efferophagosome membrane. In Aim 1, to establish the physiological significance, we will interrogate TRPM7 function across three main forms of efferocytosis, including its role in coordinating inflammatory signals. In Aim 2, we distill key insights about the nature and function of TRPM7-containing vesicles in efferophagosome maturation. In Aim 3, we develop a mechanistic picture of how TRPM7 is activated and how this activity controls efferophagosome maturation. This research is conceptually innovative because it unravels new molecular machinery involving TRPM7 in the understudied process of efferophagosome maturation. Our research is also the first thrust toward a complete biochemical characterization of TRPM7-containing vesicles (M7Vs) and their cell biological function. Technical innovations include novel transgenic/gene-edited mouse lines, and membrane fusion assays designed specifically to interrogate M7V-efferophagosome fusion. Deconstructing the efferophagosome in terms of its maturation stages, molecular architecture, and biophysical/biochemical activities may advance TRPM7 as a drug target to modify tissue regeneration and anti-viral immunity.