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Vol. 20, Issue 22, 4664-4672, November 15, 2009

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Spatiotemporal Regulation of Chloride Intracellular Channel Protein CLIC4 by RhoA

Bas Ponsioen^*, Leonie van Zeijl^*, Michiel Langeslag^*, Mark Berryman, Dene Littler, Kees Jalink^*, and Wouter H. Moolenaar^*

*Division of Cell Biology and Center for Biomedical Genetics and Division of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH 45701

Submitted June 26, 2009; Revised September 9, 2009; Accepted September 14, 2009
Monitoring Editor: J. Silvio Gutkind

Chloride intracellular channel (CLIC) 4 is a soluble protein structurally related to omega-type glutathione-S-transferases (GSTs) and implicated in various biological processes, ranging from chloride channel formation to vascular tubulogenesis. However, its function(s) and regulation remain unclear. Here, we show that cytosolic CLIC4 undergoes rapid but transient translocation to discrete domains at the plasma membrane upon stimulation of G₁₃-coupled, RhoA-activating receptors, such as those for lysophosphatidic acid, thrombin, and sphingosine-1-phosphate. CLIC4 recruitment is strictly dependent on G₁₃-mediated RhoA activation and F-actin integrity, but not on Rho kinase activity; it is constitutively induced upon enforced RhoA-GTP accumulation. Membrane-targeted CLIC4 does not seem to enter the plasma membrane or modulate transmembrane chloride currents. Mutational analysis reveals that CLIC4 translocation depends on at least six conserved residues, including reactive Cys35, whose equivalents are critical for the enzymatic function of GSTs. We conclude that CLIC4 is regulated by RhoA to be targeted to the plasma membrane, where it may function not as an inducible chloride channel but rather by displaying Cys-dependent transferase activity toward a yet unknown substrate.

Address correspondence to: Wouter H. Moolenaar (w.moolenaar{at}nki.nl)

Abbreviations used: CLIC, chloride intracellular channel; GPCR, G protein-coupled receptor; GST, glutathione transferase; LPA, lysophosphatidic acid.

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