Phagosomal acidification in macrophages enables their efficient killing of microorganisms. This is achieved by V-ATPase, which pumps protons into the phagosome, but proton accumulation results in a positive membrane potential that eventually stalls the pump. CLC exchangers relieve this positive charge through the import of Cl− ions. In a recent preprint (not peer-reviewed), Cheng et al. report an opposing ‘brake’ in this system — namely, the proton-activated chloride channel (PAC, also known as TMEM206), which exports luminal Cl− and restricts phagosomal acidification in macrophages.

The team reasoned that PAC, encoded by Pacc1, is highly expressed in macrophages and predicted to have phagosomal localization. Fluorescence imaging confirmed recruitment of PAC to phagosomes containing beads, zymosan or Escherichia coli. Notably, LPS stimulation of macrophages repressed Pacc1 transcription and channel activity, which suggests that inflammatory cues might remove PAC-mediated restraint of phagosomal acidification during infection.