Clathrin light chains are required for the gyrating-clathrin recycling pathway and thereby promote cell migration

Abstract

The clathrin light chain (CLC) subunits participate in several membrane traffic pathways involving both clathrin and actin, through binding the actin-organizing huntingtin-interacting proteins (Hip). However, CLCs are dispensable for clathrin-mediated endocytosis of many cargoes. Here we observe that CLC depletion affects cell migration through Hip binding and reduces surface expression of β1-integrin by interference with recycling following normal endocytosis of inactive β1-integrin. CLC depletion and expression of a modified CLC also inhibit the appearance of gyrating (G)-clathrin structures, known mediators of rapid recycling of transferrin receptor from endosomes. Expression of the modified CLC reduces β1-integrin and transferrin receptor recycling, as well as cell migration, implicating G-clathrin in these processes. Supporting a physiological role for CLC in migration, the CLCb isoform of CLC is upregulated in migratory human trophoblast cells during uterine invasion. Together, these studies establish CLCs as mediating clathrin–actin interactions needed for recycling by G-clathrin during migration.

Crosstalk between CLCb/Dyn1-Mediated Adaptive Clathrin-Mediated Endocytosis and Epidermal Growth Factor Receptor Signaling Increases Metastasis

“…In addition to their structural role in stabilizing clathrin triskelia, CLCs share functions in regulating HSC70, the uncoating ATPase, to disassemble clathrin cages (Schmid et al, 1984; Young et al, 2013), and interacting with HIP1 to link CCVs to the actin cytoskeleton (Chen and Brodsky, 2005; Legendre-Guillemin et al, 2005). A recent study showed that CLCs also modulate a gyrating clathrin structure that mediates the rapid recycling of transferrin receptors (TfnRs) and β1-integrin (Majeed et al, 2014) from early endosomes. Identifying CLC isoform-specific functions has been difficult given their apparently random association with triskelia (Kirchhausen et al, 1983) and substoichiometry with CHC in non-neuronal cells (Borner et al, 2012; Girard et al, 2005).…”

Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

“…Variations in cargo crowding and local lipid organization affect membrane-bending properties, which in turn require different coat properties for deformation into a vesicle (35). CLCs contribute tensile strength to the clathrin lattice through controlling the rigidity of the hub region of the triskelion (8,9) and, in cells, by recruiting the actin-regulating Hip proteins (2,6,8,15). Thus, CLCs may contribute to uptake of cargoes that pose particular membranebending challenges.…”

“…Vertebrates have two CLC isoforms, CLCa and CLCb, encoded by separate genes, CLTA and CLTB (1). Depletion of both isoforms from tissue culture cells by siRNA treatment showed that CLCs are not required for clathrin-mediated uptake of classic CCV cargoes, such as transferrin receptor (TfR), epidermal growth factor receptor, or low-density lipoprotein receptor (2)(3)(4). CLCs were, however, implicated in uptake of three G protein-coupled receptors (GPCRs) (5).…”

“…Mammalian cell culture experiments and genetic studies in yeast and flies have shown that, through these interactions, CLCs participate in several pathways that could significantly affect clathrin function in vertebrates. These pathways include clathrin-mediated endocytosis from membranes under tension (14,15), formation of clathrin-actin interfaces during cell adhesion (16), clathrin-mediated recycling in cell migration (2), and endosome function during Drosophila eye development (13).…”

Use of Gene Expression Analysis for Discrimination of Primary and Secondary Adenocarcinoma of the Liver

“…The potential function of this gene in cholangiocarcinogenesis is not known; until now there are no reports on overexpression of the gene or its protein in ICC. LCTB may play a physiological role in cell migration and may thereby be upregulated during cell invasion [23].…”