title: Intracellular chloride channel protein CLIC1 regulates macrophage function through modulation of phagosomal acidification.
abstract: Intracellular chloride channel protein 1 (CLIC1) is a 241 amino acid protein of the glutathione S transferase fold family with redox- and pH-dependent membrane association and chloride ion channel activity. Whilst CLIC proteins are evolutionarily conserved in Metazoa, indicating an important role, little is known about their biology. CLIC1 was first cloned on the basis of increased expression in activated macrophages. We therefore examined its subcellular localisation in murine peritoneal macrophages by immunofluorescence confocal microscopy. In resting cells, CLIC1 is observed in punctate cytoplasmic structures that do not colocalise with markers for endosomes or secretory vesicles. However, when these macrophages phagocytose serum-opsonised zymosan, CLIC1 translocates onto the phagosomal membrane. Macrophages from CLIC1(-/-) mice display a defect in phagosome acidification as determined by imaging live cells phagocytosing zymosan tagged with the pH-sensitive fluorophore Oregon Green. This altered phagosomal acidification was not accompanied by a detectable impairment in phagosomal-lysosomal fusion. However, consistent with a defect in acidification, CLIC1(-/-) macrophages also displayed impaired phagosomal proteolytic capacity and reduced reactive oxygen species production. Further, CLIC1(-/-) mice were protected from development of serum transfer induced K/BxN arthritis. These data all point to an important role for CLIC1 in regulating macrophage function through its ion channel activity and suggest it is a suitable target for the development of anti-inflammatory drugs.
authors.affiliation: St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia. l.jiang@amr.org.au
authors.forename: Lele
authors.initials: L
authors.lastname: Jiang
authors.forename: Kanin
authors.initials: K
authors.lastname: Salao
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Rybicka
authors.forename: Robin M
authors.initials: RM
authors.lastname: Yates
authors.forename: Xu Wei
authors.initials: XW
authors.lastname: Luo
authors.forename: Xin Xin
authors.initials: XX
authors.lastname: Shi
authors.forename: Tamara
authors.initials: T
authors.lastname: Kuffner
authors.forename: Vicky Wang-Wei
authors.initials: VW
authors.lastname: Tsai
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Husaini
authors.forename: Liyun
authors.initials: L
authors.lastname: Wu
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Brown
authors.forename: Paul M G
authors.initials: PM
authors.lastname: Curmi
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
mesh_terms: D000143:Acids / Q000378:metabolism*; D000818:Animals; D001168:Arthritis / Q000378:metabolism / Q000473:pathology; D018118:Chloride Channels / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006016:Glycolates / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein; D000099149:Ezrin
chemical_list: D000143:Acids; D018118:Chloride Channels; D003598:Cytoskeletal Proteins; D006016:Glycolates; D008565:Membrane Proteins; D008840:Microfilament Proteins; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; D000099149:Ezrin; C501967:Clic1 protein, mouse; C071058:moesin; C071776:radixin; C015765:MK 473