The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes

Nature. 2008 Jun 5;453(7196):788-92. doi: 10.1038/nature06907. Epub 2008 Apr 30.


Lysosomes are the stomachs of the cell-terminal organelles on the endocytic pathway where internalized macromolecules are degraded. Containing a wide range of hydrolytic enzymes, lysosomes depend on maintaining acidic luminal pH values for efficient function. Although acidification is mediated by a V-type proton ATPase, a parallel anion pathway is essential to allow bulk proton transport. The molecular identity of this anion transporter remains unknown. Recent results of knockout experiments raise the possibility that ClC-7, a member of the CLC family of anion channels and transporters, is a contributor to this pathway in an osteoclast lysosome-like compartment, with loss of ClC-7 function causing osteopetrosis. Several mammalian members of the CLC family have been characterized in detail; some (including ClC-0, ClC-1 and ClC-2) function as Cl--conducting ion channels, whereas others act as Cl-/H+antiporters (ClC-4 and ClC-5). However, previous attempts at heterologous expression of ClC-7 have failed to yield evidence of functional protein, so it is unclear whether ClC-7 has an important function in lysosomal biology, and also whether this protein functions as a Cl- channel, a Cl-/H+ antiporter, or as something else entirely. Here we directly demonstrate an anion transport pathway in lysosomes that has the defining characteristics of a CLC Cl-/H+ antiporter and show that this transporter is the predominant route for Cl- through the lysosomal membrane. Furthermore, knockdown of ClC-7 expression by short interfering RNA can essentially ablate this lysosomal Cl-/H+ antiport activity and can strongly diminish the ability of lysosomes to acidify in vivo, demonstrating that ClC-7 is a Cl-/H+ antiporter, that it constitutes the major Cl- permeability of lysosomes, and that it is important in lysosomal acidification.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antiporters / deficiency
  • Antiporters / genetics
  • Antiporters / metabolism*
  • Chloride Channels / deficiency
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Chlorides / metabolism*
  • Fluorescence
  • HeLa Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Ion Transport
  • Liver / cytology
  • Liver / metabolism
  • Lysosomes / metabolism*
  • Permeability
  • Protons
  • Rats


  • Antiporters
  • CLCN7 protein, human
  • Chloride Channels
  • Chlorides
  • Protons
  • hydrogen-chloride symporter