Planells-Cases Rosa, Vorobeva Viktoriia, Kar Sumanta, Schmitt Franziska W, Schulte Uwe, Schrecker Marina, Hite Richard K, Fakler Bernd, Jentsch Thomas J
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
Graduate Program of the Free University Berlin, Berlin, Germany.
Nat Commun. 2025 Apr 1;16(1):3117. doi: 10.1038/s41467-025-58546-3.
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. Inhibition requires a carboxy-terminal TMEM9 domain that interacts with CLCs at multiple sites. Disease-causing CLCN mutations that weaken inhibition by TMEM9 proteins cause a pathogenic gain of ion transport. Our work reveals the need to suppress, in a regulated manner, endolysosomal chloride/proton exchange. Several aspects of endosomal ion transport must be revised.
内体的功能严重依赖于其离子稳态。除了H⁺外，腔内Cl⁻的关键作用也越来越受到认可。这两种离子都由五种不同的内溶酶体CLC氯化物/质子交换体转运。这些转运蛋白中的每一种功能失调都会导致严重疾病。在这里，我们确定TMEM9和TMEM9B是内体ClC-3、ClC-4和ClC-5的必需β亚基。缺乏这两种β亚基的小鼠所有三种CLC的水平都严重降低，并在胚胎期或出生后不久死亡。TMEM9蛋白调节其伙伴的运输。令人惊讶的是，它们还强烈抑制CLC离子运输。持续性抑制能够调节CLC，并防止内体中有毒的Cl⁻积累和肿胀。抑制需要一个羧基末端的TMEM9结构域，该结构域在多个位点与CLC相互作用。削弱TMEM9蛋白抑制作用的致病CLCN突变会导致离子运输的致病性增加。我们的工作揭示了以一种受调控的方式抑制内溶酶体氯化物/质子交换的必要性。内体离子运输的几个方面必须重新审视。
