Clathrin-independent carrier pathway (CLIC pathway)

The Clathrin-independent carrier (CLIC) pathway, also known as the CLIC/GEEC pathway, is a high-capacity endocytic route responsible for the bulk uptake of fluid, membrane, and glycosylphosphotidylinositol-anchored proteins (GPI-APs). This pathway is primarily regulated by the small GTPase CDC42 and is characterized by its independence from the clathrin coat and, frequently, the scission protein dynamin. It matures into the GPI-anchored protein-enriched early endocytic compartment (GEEC) and plays essential roles in cellular homeostasis, plasma membrane repair, and cytokinesis. In pathology, the CLIC pathway is hijacked by viruses such as HIV-1 to establish intracellular reservoirs in macrophages and is implicated in cancer progression and metastasis through the regulation of cell migration and chemoresistance. Proteins within this pathway, particularly CLIC1 and CLIC4, also function as critical modulators of the NLRP3 inflammasome and G protein-coupled receptor (GPCR) signaling, making them attractive targets for inflammatory and cardiovascular therapies. Current research focuses on small-molecule inhibitors of CDC42 and associated proteins like PICK1 to disrupt these pathogenic processes.

Other names

CLIC/GEEC pathwayCG pathwayCdc42-mediated clathrin-independent endocytosisClathrin-independent carriers pathwayChloride intracellular channel pathway

Inhibition of the CLIC pathway is achieved through allosteric inhibition of the small GTPase CDC42 (the primary regulator of vesicle formation), blockade of the PICK1 PDZ domain to prevent endocytic cargo sorting, and direct inhibition or blockade of chloride intracellular channel proteins (CLIC1/CLIC4) to prevent membrane translocation and activation of the NLRP3 inflammasome.