Essential role of an acidic endosomal environment in JAK3-mediated signal transduction

The endosome, an acidic organelle, is a platform for endocytic trafficking and signal transduction. Chloroquine, an intercellular acidic vesicle neutralizer (IAVN), has been used to treat autoimmune diseases. Its immunosuppressive mechanism remains unclear, although several modes of action attributable to lysosomal dysfunction have been postulated. This study found that IAVNs, including chloroquine, can selectively interfere with common cytokine receptor γ chain (γc) cytokine-induced signal transduction. Our data show that JAK3 targets endosomal membranes in an acidic pH-dependent manner, which is essential for γc-cytokine-induced functional signal complex formation and signal activation. Among IAVNs, Monensin and similar ionophores were particularly effective in suppressing γc-cytokine-induced cell proliferation in vitro. Monensin exerted therapeutic effects in a collagen-induced arthritis mouse model by interfering with T helper 17 cells. Our findings help further understand the immunosuppressive mechanism of IAVNs and unveil the spatial regulation of JAK3-mediated signal transduction via endosomes.