CLIC proteins, ezrin, radixin, moesin and the coupling of membranes to the actin cytoskeleton: A smoking gun?

Abstract

The CLIC proteins are a highly conserved family of metazoan proteins with the unusual ability to adopt both soluble and integral membrane forms. The physiological functions of CLIC proteins may include enzymatic activity in the soluble form and anion channel activity in the integral membrane form. CLIC proteins are associated with the ERM proteins: ezrin, radixin and moesin. ERM proteins act as cross-linkers between membranes and the cortical actin cytoskeleton. Both CLIC and ERM proteins are controlled by Rho family small GTPases. CLIC proteins, ERM and Rho GTPases act in a concerted manner to control active membrane processes including the maintenance of microvillar structures, phagocytosis and vesicle trafficking. All of these processes involve the interaction of membranes with the underlying cortical actin cytoskeleton. The relationships between Rho GTPases, CLIC proteins, ERM proteins and the membrane:actin cytoskeleton interface are reviewed. Speculative models are proposed involving the formation of localised multi-protein complexes on the membrane surface that assemble via multiple weak interactions. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.

Clustered phosphatidylinositol 4,5 bisphosphate accumulation and ezrin phosphorylation in response to CLIC5A

“…CLIC and ERM proteins are commonly associated (Jiang et al, 2014), and both CLIC5A and CLIC4 have been shown previously to associate with ezrin and to induce cell surface microvillus formation in epithelial cells (Berryman et al, 2004;Viswanatha et al, 2013). However, the mechanism(s) governing the functional interactions between CLICs and ERM proteins are not understood.…”

Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

“…9 Secondly, Clic5 functions as an adapter between the plasma membrane of podocytes and the actin cytoskeleton by facilitating the interaction between ezrin and podocalyxin. 17,18,23 Thirdly, a recent study proposes that Clic5 functions as part of a multiprotein linker complex in companion with radixin, erzin and taperin. 24 Protein tyrosine phosphatase receptor Q (Ptprq), which is mislocalized as radixin in the jbg mice, and Myosin VI, key regulator of the proper localization of Ptprq, 25 might well participate in this complex too.…”

Emerging biological roles of Cl− intracellular channel proteins

“…It was purified from bovine kidney microsomes as a protein that binds to the putative Cl − channel inhibitor indaloxyacetic acid-94 (IAA94) (Landry et al, 1989), but sequence analysis revealed that p64 was not a conventional Cl − channel (see Box 1). Over the years, other p64-related mammalian proteins were identified that now make up the CLIC family, which consists of six distinct paralogues, termed CLIC1 through to CLIC6 (Dulhunty et al, 2001;Harrop et al, 2001;Heiss and Poustka, 1997;Jiang et al, 2014;Littler et al, 2005Littler et al, , 2010 (Fig. 1A).…”

“…However, the ion channel hypothesis remains speculative because there is no convincing evidence of CLICs having ion channel activity under physiological conditions (see Box 1). In terms of cellular function, CLICs are often found associated with the cortical actin cytoskeleton (Berryman and Bretscher, 2000;Berryman et al, 2004;Jiang et al, 2014) and are detected on intracellular membranes, where they may participate in the formation and maintenance of vesicular compartments; but it is still unclear as to how this function is achieved mechanistically. Growing evidence indicates that CLIC proteins have roles in dynamic actin-dependent trafficking events, during which they can undergo rapid redistribution between subcellular locations in response to agonist stimulation (Ponsioen et al, 2009;Shukla et al, 2009).…”

“…Moreover, they show intrinsic glutaredoxinlike activity in vitro (Al Khamici et al, 2015). Although genetargeting studies have begun to reveal the essential, non-redundant physiological roles of the CLIC proteins, their inner workings and biochemical functions still remain enigmatic (Jiang et al, 2014;Littler et al, 2010).…”