lysosomal p1

How are signals of extracellular stress relayed to lysosomes?

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We have previously demonstrated that the key lysosomal transcription factors, Tfeb and Tfe3, activate lysosomal pathways in microglia and macrophages specifically in response to extracellular stress in zebrafish. Our findings question the established view that these transcription factors are required for basal lysosomal activity and reveal mechanisms using which macrophages can turn on endolysosomal signaling when challenged with immunological triggers. Our observation that macrophages have a dedicated, conserved signaling pathway to deploy lysosomal activation in response to stress led us to investigate the molecular mechanisms using which macrophages sense a wide range of environmental stress cues and transmit them to lysosomes. We believe that a broad understanding of how brain and peripheral macrophages respond to stress in vivo will be important to enhance our knowledge of infection, repair, aging, and other processes that hinge upon macrophage stress responses.

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lysosomal p2

What are the key molecular differences in the endolysosomal pathway between professional and non-professional phagocytic cells?

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Although multiple cell types are equipped with the ability to perform phagocytosis in invertebrates, in vertebrates, this indispensable task is delegated to the professional phagocytes, including microglia and macrophages. Indeed, it has been shown that circulating monocytes, the progenitors of tissue-resident macrophages, have limited phagocytic capacity, thus indicating that the ability to phagocytose is acquired during development and through differentiation. We are fascinated by multiple open-ended questions in the field of phagocytosis: Are there molecular signals that are necessary and sufficient to endow phagocytic capacity to cells? Is the endolysosomal cascade conserved between phagocytic and non-phagocytic cell populations? Do non-professional phagocytes, such as epithelial cells, lose their phagocytic potential as development progresses? What are the “find-me”, “eat-me”, and “don’t-eat-me signals” in play during “phagoptosis” (cell death by phagocytosis), and how is this delicate process regulated?

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