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.

History

20POST35120556