Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor-mediated endocytosis.
Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor-mediated endocytosis.
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DOI：
10.1016/j.celrep.2020.108683
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发表时间：
2021-01-26
期刊：
影响因子：
8.8
通讯作者：
Qiu Z
中科院分区：
文献类型：
--
作者：
Osei-Owusu J;Yang J;Leung KH;Ruan Z;Lü W;Krishnan Y;Qiu Z
在囊泡酸化过程中，氯离子（Cl −）作为抗衡离子，为液泡H + ATP酶的质子泵送提供电分流。细胞内CLC转运蛋白通过其2Cl −/H+交换活性介导Cl −流入内溶酶体。然而，全内溶酶体膜片钳记录也揭示了一个神秘的电导释放Cl −从管腔。目前尚不清楚是否CLC或其他Cl −通道负责这种活动。在这里，我们表明，新发现的质子激活的Cl −（PAC）通道交通从质膜到内涵体通过经典的YxxL基序。PAC缺失消除了内体Cl −传导，提高了管腔Cl −水平，降低了管腔pH，并增加了转铁蛋白受体介导的内吞作用。PAC过表达产生大的内体Cl −电流，其性质与内源性电导相似，使内体pH低酸化，并减少转铁蛋白摄取。我们提出，内体Cl − PAC通道作为低pH传感器发挥作用，并通过从内腔释放Cl −来防止过度酸化。Osei-Owusu等人表明，最近发现的质子激活氯离子（PAC）通道从质膜运输到内体，并形成细胞内细胞器Cl −通道。PAC在核内体中起低pH传感器的作用，并防止管腔过度酸化。
During vesicular acidification, chloride (Cl−), as the counterion, provides the electrical shunt for proton pumping by the vacuolar H+ ATPase. Intracellular CLC transporters mediate Cl− influx to the endolysosomes through their 2Cl−/H+ exchange activity. However, whole-endolysosomal patch-clamp recording also revealed a mysterious conductance releasing Cl− from the lumen. It remains unknown whether CLCs or other Cl− channels are responsible for this activity. Here, we show that the newly identified proton-activated Cl− (PAC) channel traffics from the plasma membrane to endosomes via the classical YxxL motif. PAC deletion abolishes the endosomal Cl− conductance, raises luminal Cl− level, lowers luminal pH, and increases transferrin receptor-mediated endocytosis. PAC overexpression generates a large endosomal Cl− current with properties similar to those of endogenous conductance, hypo-acidifies endosomal pH, and reduces transferrin uptake. We propose that the endosomal Cl− PAC channel functions as a low pH sensor and prevents hyper-acidification by releasing Cl− from the lumen. Osei-Owusu et al. show that the recently identified proton-activated chloride (PAC) channel traffics from the plasma membrane to endosomes and forms an intracellular organelle Cl− channel. PAC functions as a low pH sensor in endosomes and prevents luminal hyper-acidification.
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