Journal
CELL REPORTS
Volume 34, Issue 4, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108683
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Funding
- AHA [20POST35120556, 18PRE34060025]
- American Brain Foundation postdoctoral fellowship [20POST35200185]
- Orphan Disease Center at the University of Pennsylvania [MDBR-19-123-NPC-6-34637]
- National Institutes of Health (NIH) [R01NS112363, R01NS112139-01A1, R21NS114428, R35GM124824, R01NS118014]
- McKnight Scholar award
- Sloan Research Fellowship in Neuroscience
- Klingenstein-Simon Scholar award
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The proton-activated Cl- (PAC) channel has been identified as a low pH sensor in endosomes, preventing hyper-acidification by releasing Cl- from the lumen.
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 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.
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