FIGURE 6.

Lysosome adaptation and remodeling during immune responses. (A) Cytokine and TLR signaling stimulate mTORC1, likely by suppressing TSC using Akt and IKKβ. Among other functions, LPS-TLR4 activation of mTORC1 may stimulate the levels of Arl8b on lysosomes, which coordinates with kinesin-1 to drive lysosome tubulation and extension towards the cell periphery. This may then aid in antigen presentation in dendritic cells. Tubulation may also aid in increasing the surface area-to-volume ratio of lysosomes to favor antigen processing and export or other functions. For example, the SLC15A3/4 transporters export muramyl dipeptides originating from gram-positive bacteria to induce NOD signaling. (B) During phagocytosis, microbes are engulfed and sequestered into phagosomes. Engulfment is aided by lysosome exocytosis triggered by release of lysosomal Ca²⁺ via TRPML1. Phagosomes then mature by fusing with lysosomes to digest the particle. Phagosome-lysosome fusion is catalyzed by TRPML1-mediated Ca²⁺ release from lysosomes as well. TFEB is activated by LPS-TLR4 signaling in a delayed fashion or by phagocytosis of bacteria. During phagosome maturation, TRPML1-mediated Ca²⁺ elicits nuclear entry of TFEB to upregulate lysosome gene expression, enhancing the degradative and killing capacity of macrophages. In dendritic cells, TFEB activation enhances TRPML1 expression, which aids in intralysosomal Ca²⁺ release that coordinates the acto-myosin machinery to facilitate dendritic cell migration.