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Cl− intracellular channels (CLICs) are a family of six evolutionary conserved cytosolic proteins that exist in both soluble and membrane-associated forms; however, their functions have long been elusive. Soluble CLICs adopt a glutathione S-transferase (GST)-fold, can induce ion currents in artificial membranes and show oxidoreductase activity in vitro, but there is no convincing evidence of CLICs having such activities in vivo. Recent studies have revealed a role for CLIC proteins in Rho-regulated cortical actin dynamics as well as vesicular trafficking and integrin recycling, the latter of which are under the control of Rab GTPases. In this Commentary, we discuss the emerging roles of CLIC proteins in these processes and the lessons learned from gene-targeting studies. We also highlight outstanding questions regarding the molecular function(s) of these important but still poorly understood proteins.

Chloride intracellular channel (CLIC) protein CLIC4 exists in both soluble and membrane-associated forms, and is implicated in diverse cellular processes, ranging from ion channel formation to intracellular membrane remodeling. CLIC4 is rapidly recruited to the plasma membrane by lysophosphatidic acid (LPA) and serum, suggesting a possible role for CLIC4 in exocytic-endocytic trafficking. However, the function and subcellular target(s) of CLIC4 remain elusive. Here we show that in HeLa and MDA-MB-231 cells, CLIC4 knockdown decreases cell-matrix adhesion, cell spreading and integrin signalling, while increasing cell motility. LPA stimulates the recruitment of CLIC4 to β1 integrins at the plasma membrane and in Rab35-positive endosomes. CLIC4 is required for both the internalization and the serum/LPA-induced recycling of β1 integrins, but not for EGF receptor trafficking. Furthermore, we show that CLIC4 suppresses Rab35 activity and antagonizes Rab35-dependent regulation of β1-integrin trafficking. Our results define CLIC4 as a regulator of Rab35 activity and serum/LPA-dependent integrin trafficking.