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Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor- mediated endocytosis

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journal contribution
posted on 2021-03-12, 23:52 authored by James Osei-Owusu, Junhua Yang, Ka Ho Leung, Zheng Ruan, Wei Lü, Yamuna Krishnan, Zhaozhu Qiu
During vesicular acidification, chloride (Cl ), as the counterion, provides the electrical shunt for proton pump-
ing 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 re-
vealed 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 trans-
ferrin 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 trans-
ferrin 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.


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