How are signals of extracellular stress relayed to lysosomes?

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.

Using genome-wide CRISPR screens, we will uncover molecular players that activate lysosomal pathways when macrophages are challenged with debris in the form of synaptosomes, myelin fragments, or misfolded proteins. Our experiments will reveal both Tfeb and Tfe3-dependent and independent mechanisms using which macrophages cope with extracellular stress.