Abstract
CLIC4 and CLIC1 are members of the well-conserved chloride intracellular channel proteins (CLICs) structurally related to glutathione-S-transferases. Here, we report new roles of CLICs in cytokinesis. At the onset of cytokinesis, CLIC4 accumulates at the cleavage furrow and later localizes to the midbody in a RhoA-dependent manner. The cell cycle-dependent localization of CLIC4 is abolished when its glutathione S-transferase activity-related residues (C35A and F37D) are mutated. Ezrin, anillin, and ALIX are identified as interaction partners of CLIC4 at the cleavage furrow and midbody. Strikingly, CLIC4 facilitates the activation of ezrin at the cleavage furrow and reciprocally inhibition of ezrin activation diminishes the translocation of CLIC4 to the cleavage furrow. Furthermore, knockouts of CLIC4 and CLIC1 cause abnormal blebbing at the polar cortex and regression of the cleavage furrow at late cytokinesis leading to multinucleated cells. We conclude that CLIC4 and CLIC1 function together with ezrin where they bridge plasma membrane and actin cytoskeleton at the polar cortex and cleavage furrow to promote cortical stability and successful completion of cytokinesis in mammalian cells.
Highlights
The chloride intracellular channel (CLIC) family is composed of six members (CLIC1-6) that can exist in both soluble and membraneintegrated forms
As the sister chromatids separated at the anaphase onset, CLIC4 started disappearing from the cell poles and gradually accumulating at the cleavage furrow (Fig 1A and Video 1)
To further assess whether the cleavage furrow localization of CLIC4 is dependent on RhoA activation, HeLa S3 cells were synchronized to cytokinesis and treated with Rhosin, which inhibits the GEF activation domain of RhoA (Shang et al, 2012)
Summary
The chloride intracellular channel (CLIC) family is composed of six members (CLIC1-6) that can exist in both soluble and membraneintegrated forms. CLIC4 is the most studied member of the CLIC family and has been implicated in many actin-based cellular processes including G-protein–coupled receptor signaling, cell differentiation, adhesion, spreading, migration, integrin signaling, and protein trafficking (Ponsioen et al, 2009; Argenzio et al, 2014, 2018; Shukla et al, 2014; Chou et al, 2016). Cytosolic CLIC4 was shown to transiently translocate to the plasma membrane upon serum or lysophosphatidic acid (LPA)–induced RhoA activation in an F-actin–dependent manner (Ponsioen et al, 2009). CLIC4 is recruited to β1-integrin at the plasma membrane upon LPA stimulation, and its knockdown causes a reduced integrinmediated cell adhesion and increased motility (Argenzio et al, 2014)
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