Author response: Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells

TRP Channels as Interior Designers: Remodeling the Endolysosomal Compartment in Natural Killer Cells

“…From all three members of the mucolipin subfamily, TRPML2 shows the most limited tissue distribution, compared to the other members of the subfamily (146). Based on electrophysiological data, TRPML2 activity is reduced at low luminal pH and reaches its maximum at neutral luminal pH (24). TRPML2 can be activated as previously introduced for TRPML1, by the phosphatidylinositol-(3,5)-phosphate PI(3,5)P2 (131,147).…”

“…In this context, TRP channels represent promising targets for manipulation by means of pharmacological or genetic perturbation (25). The mucolipin subfamily of TRP cation channels could potentially be targeted to modify the rate of lysosomal biogenesis or, as described for TRPML2 in macrophages, to modulate the secretion of chemokines in immune effector cells (24,151). It may also be possible to build functional potential in lymphocytes through manipulation of the lysosomal matrix, which influence loading of positively charged effector molecules such as granzyme B as well as calcium (181,182).…”

“…Both TRPML2 and 3, in contrast to TRPML1 reside in early and recycling endosomal compartments hence would be exposed to less acidic conditions. In conclusion, the early endosomal and recycling endosomes provide a neutral pH, which promotes TRPML2 activity (24).…”

“…In murine macrophages TRPML2 expression is connected to activation status and modulates the recruitment and chemokine secretion in response to proinflammatory stimuli. The latter effect has been shown by knockout studies and upon specific pharmacological intervention (24,151). There are many outstanding questions regarding the role of the intracellular TRPML2 localization and its impact on TRPML1 activity and effector functions in general.…”

“…A multitude of metabolites can be exchanged via physical inter-organelle contact sites, which, in turn, influences calcium channel activity, and can help to coordinate calcium homeostasis, in order to establish proper immune cell responses. In cytotoxic lymphocytes, changes in the lysosomal signaling capacity directly correlates with immune cell effector responses (20)(21)(22)(23)(24)(25). Therefore, lysosomal calcium channels emerge as novel targets for genetic and pharmacological interventions aiming to boost immune effector cell function in cancer immunotherapy.…”