Publication Date:
2008-05-02
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graves, Austin R -- Curran, Patricia K -- Smith, Carolyn L -- Mindell, Joseph A -- Intramural NIH HHS/ -- England -- Nature. 2008 Jun 5;453(7196):788-92. doi: 10.1038/nature06907. Epub 2008 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Membrane Transport Biophysics Unit, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Building 35, MSC 3701, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18449189" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antiporters/deficiency/genetics/*metabolism
;
Chloride Channels/deficiency/genetics/*metabolism
;
Chlorides/*metabolism
;
Fluorescence
;
HeLa Cells
;
Humans
;
Hydrogen-Ion Concentration
;
Ion Transport
;
Liver/cytology/metabolism
;
Lysosomes/*metabolism
;
Permeability
;
Protons
;
Rats
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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