Abstract
We generated and studied CLIC1 null (C1KO) mice to investigate the physiological role of this protein. C1KO and matched wild‐type (WT) mice were studied in two models of acute toxic tissue injury. CLIC1 expression is upregulated following acute injury of WT kidney and pancreas and is absent in C1KOs. Acute tissue injury is attenuated in the C1KOs and this correlates with an absence of the rise in tissue reactive oxygen species (ROS) that is seen in WT mice. Infiltration of injured tissue by inflammatory cells was comparable between WT and C1KOs. Absence of CLIC1 increased PMA‐induced superoxide production by isolated peritoneal neutrophils but dramatically decreased PMA‐induced superoxide production by peritoneal macrophages. CLIC1 is expressed in both neutrophils and macrophages in a peripheral pattern consistent with either plasma membrane or the cortical cytoskeleton in resting cells and redistributes away from the periphery following PMA stimulation in both cell types. Absence of CLIC1 had no effect on redistribution or dephosphorylation of Ezrin/ERM cytoskeleton in macrophages. Plasma membrane chloride conductance is altered in the absence of CLIC1, but not in a way that would be expected to block superoxide production. NADPH oxidase redistributes from an intracellular compartment to the plasma membrane when WT macrophages are stimulated to produce superoxide and this redistribution fails to occur in C1KO macrophages. We conclude that the role of CLIC1 in macrophage superoxide production is to support redistribution of NADPH oxidase to the plasma membrane, and not through major effects on ERM cytoskeleton or by acting as a plasma membrane chloride channel.
Highlights
The CLICs are a closely related family of proteins whose physiological roles in health and disease remain a matter of intense debate (Littler et al 2010)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
If the resulting message is stable, the disrupted Clic1 gene would encode a 1649 MW protein that consists of the N-terminal 13 amino acids of CLIC1 encoded by exon 1, followed by 1 amino acid encoded by the second reading of exon 5
Summary
The CLICs are a closely related family of proteins whose physiological roles in health and disease remain a matter of intense debate (Littler et al 2010). CLICs were initially identified and described as chloride channels of intracellular compartments (Landry et al 1993; Valenzuela et al 1997), and several groups have demonstrated that purified recombinant CLIC proteins can confer ion permeability to phospholipid membranes (Duncan et al 1997; Edwards et al 1998; Tonini et al 2000; Tulk et al 2002; Warton et al 2002; Berryman et al 2004; Singh et al 2007); this hypothesis has been widely challenged and definitive evidence of an endogenous CLIC clearly functioning as a channel in vivo remains elusive. Whether as ion channels or as cytoskeletal regulators, CLICs clearly play a a 2017 The Authors.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
