| Keratin 18 (K18) is a type I acidic intermediate filament protein that forms obligate heterodimers with type II keratin 8 (K8) to create the principal cytoskeletal network in simple (single-layered) epithelial tissues such as the liver, pancreas, lung, and gastrointestinal tract. K18 exhibits a canonical tripartite structure, consisting of a glycine/serine-rich N-terminal head domain (with phosphorylation sites Ser33 and Ser52 that regulate filament disassembly), a central α-helical rod domain (~312 amino acids) composed of four coiled-coil segments enabling staggered assembly into heterodimers, tetramers, protofilaments, and 10-nm filaments, and a lysine/arginine-rich C-terminal tail domain for lateral packing. K18/K8 filaments provide mechanical resilience against stress and shear, support organelle positioning (including desmosomes, nucleus, and mitochondria), and are dynamically reorganized during mitosis and apoptosis through caspase-3 cleavage (Asp238 and Asp397) and Ser33 phosphorylation, which can lead to cytoplasmic aggregate formation. K18 also modulates signaling pathways (such as 14-3-3ε, Nox4, and Nrf2) for protection against reactive oxygen species. Clinically, K18 serves as a biomarker for adenocarcinomas (via circulating M30/M65 fragments), and mutations (e.g., p.Ala282Asp, p.Leu127Pro) are linked to filament aggregation, cryptogenic cirrhosis, and increased risk of hepatocellular carcinoma. |
