Endosomal chloride/proton exchangers need inhibitory TMEM9 β-subunits for regulation and prevention of disease-causing overactivity.

ABSTRACT: The function of endosomes critically depends on their ion homeostasis. A crucial role of luminal Cl^-, in addition to that of H⁺, is increasingly recognized. Both ions are transported by five distinct endolysosomal CLC chloride/proton exchangers. Dysfunction of each of these transporters entails severe disease. Here we identified TMEM9 and TMEM9B as obligatory β-subunits for endosomal ClC-3, ClC-4, and ClC-5. Mice lacking both β-subunits displayed severely reduced levels of all three CLCs and died embryonically or shortly after birth. TMEM9 proteins regulate trafficking of their partners. Surprisingly, they also strongly inhibit CLC ion transport. Tonic inhibition enables the regulation of CLCs and prevents toxic Cl^- accumulation and swelling of endosomes. I

SUBMITTER: Planells-Cases R 

PROVIDER: S-EPMC11962092 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature