Abstract
Cytotoxic lymphocytes, including natural killer (NK) cells and T cells are distinguished by their ability to eliminate target cells through release of secretory lysosomes. Conventional lysosomes and secretory lysosomes are part of the pleomorphic endolysosomal system and characterized by its highly dynamic nature. Several calcium-permeable TRP calcium channels play an essential role in endolysosomal calcium signaling to ensure proper function of these organelles. In NK cells, the expression of self MHC-specific inhibitory receptors dynamically tunes their secretory potential in a non-transcriptional, calcium-dependent manner. New insights suggest that TRPML1-mediated lysosomal calcium fluxes are tightly interconnected to NK cell functionality through modulation of granzyme B and perforin content of the secretory lysosome. Lysosomal TRP channels show a subset-specific expression pattern during NK differentiation, which is paralleled with gradually increased loading of effector molecules in secretory lysosomes. Methodological advances, including organellar patch-clamping, specific pharmacological modulators, and genetically-encoded calcium indicators open up new possibilities to investigate how TRP channels influence communication between intracellular organelles in immune cells. This review discusses our current understanding of lysosome biogenesis in NK cells with an emphasis on the TRP mucolipin family and the implications for NK cell functionality and cancer immunotherapy.
Highlights
Reviewed by: Qiong Gao, University of Michigan, United States Michael X
The importance of calcium signals derived from the acidic, endolysosomal calcium stores, as a basis for communication between organelles and coordination of metabolism and transport processes has become increasingly appreciated in the context of disease and immune cell function [16,17,18,19]
This review focus on the role of transient receptor potential (TRP) calcium channels in the remodeling of the endolysosomal compartment in natural killer (NK) cells and in orchestrating organelle communication in cytotoxic lymphocytes
Summary
Channels as Interior Designers: Remodeling the Endolysosomal Compartment in Natural Killer Cells. TRP Channels in NK Cells specific genetic alterations, cellular stress, or intracellular retention by viral proteins This potential loophole of the body’s defense is guarded by natural killer (NK) cells that express MHC binding inhibitory receptors. The importance of calcium signals derived from the acidic, endolysosomal calcium stores, as a basis for communication between organelles and coordination of metabolism and transport processes has become increasingly appreciated in the context of disease and immune cell function [16,17,18,19]. Lysosomal calcium channels emerge as novel targets for genetic and pharmacological interventions aiming to boost immune effector cell function in cancer immunotherapy. This review focus on the role of transient receptor potential (TRP) calcium channels in the remodeling of the endolysosomal compartment in NK cells and in orchestrating organelle communication in cytotoxic lymphocytes. TPC biology and their role in the endolysosomal system are reviewed elsewhere [27, 28]
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