Revealing the secrets of secretion

Abstract

An intracellular ion channel may have a central role in the release of cytokines by macrophages.

Keywords: CCL2; TRPML2; biochemistry; chemical biology; cytokine; endosome; macrophage; mouse; secretion.

Figure 1.. The activation of an intracellular channel promotes the trafficking and secretion of a cytokine.

The binding of lipopolysaccharides (LPS) to toll-like receptors (TLR4) on the surface of a macrophage leads to the synthesis of the cytokine CCL2 (pale blue disks) and the ion channel TRPML2 in the nucleus and the rough endoplasmic reticulum (rER). CCL2 is then trafficked to the Golgi apparatus (TGN) and onwards inside vesicles (black circles) to the early endosome (EE) and the recycling endosome (RE), before it is secreted by the cell. This secretory pathway involves the vesicles being formed in a fission process, and then fusing with the next compartment in the pathway. The ion channel TRPML2 allows the passage of calcium ions (Ca²⁺) across the membranes of the compartments (blue arrows). This results in fluxes of vesicular Ca²⁺, which are thought to participate in the control of both the fission and fusion of transport vesicles, including the final step that sees CCL2 released into the environment. TRPML2 does not work in highly acidic conditions (deep red), so late endosomes and lysosomes (LE/LY) are unlikely to be regulated by this channel. However, early endosomes (EE) and recycling endosomes (RE) are less acidic (pale red and blue), and they may be hosting this cytokine. The vesicles that fuse with the external membrane of the macrophage to secrete CCL2 are therefore likely to be of endosomal origin, rather than specialized secretory granules. When added to macrophages, the small molecule ML2-SA1 (top) selectively opens TRPML2 channels – as assessed by electrical measurements on endosomes (left of figure) – and promotes CCL2 secretion.