Keratins, formerly known as cytokeratins, are the major epithelial‐specific subgroup of intermediate filament proteins. Adult hepatocytes express keratin polypeptides 8 and 18 (K8/K18), whereas cholangiocytes express K8/K18 and keratins 7 and 19 (K7/K19). Keratins function primarily to protect hepatocytes from apoptosis and necrosis, which was revealed using several genetic mouse models. This cytoprotective function was further clarified by the identification of natural human keratin variants that are normally silent, but become pathogenic by predisposing their carriers to apoptosis during acute or chronic liver injury mediated by toxins, virus infection, or metabolic stress. During apoptosis, caspases cleave K18 and K19 at conserved aspartates (human K18/K19:²³⁵Val‐Glu‐Val‐Asp^↓) and K18 at a unique aspartate (human K18:³⁹⁴Asp‐Ala‐Leu‐Asp^↓), with the latter exposed epitope becoming recognized by the M30 antibody in blood and tissues. Additional K18‐containing protein backbone epitopes are detected using the M6 and M5 (termed M65) antibodies. Intact K18 and its associated fragments, which are released into blood during apoptosis and necrosis in various diseases, have been analyzed by enzyme‐linked immunosorbent assay using the M30/M65 antibodies or their signal ratios. Furthermore, M30/M65 levels have been used as diagnostic and prognostic biomarkers in acute and chronic liver diseases, including nonalcoholic steatohepatitis and acute liver failure. Other keratin biomarkers include K8/K18/K19‐related tissue polypeptide antigen, K18‐related tissue polypeptide‐specific antigen, and K19‐related CYFRA‐21‐1, which have been evaluated mostly in patients with epithelial tumors.Conclusion: Keratins and their fragments are released into blood during liver and other epithelial tissue injury. The epithelial specificity of K18/K19, epitope unmasking upon caspase digestion, keratin abundance, and relative keratin stability render them useful biomarkers for hepatocyte and cholangiocyte apoptosis and necrosis. However, the precise biochemical nature and release mechanism of circulating keratins remain unknown. (Hepatology2016;64:966‐976)

A protein modification called O-linked glycosylation regulates the interactions between vimentin molecules under normal conditions, and the ability of Chlamydia bacteria to replicate after they infect cells.

Keratins make up a major portion of epithelial intermediate filament proteins. The widely diverse keratins are found in both the small and large intestines. The human intestine mainly expresses keratins 8, 18, 19, and 20. Many of the common roles of keratins are for the integrity and stability of the epithelial cells. The keratins also protect the cells and tissue from stress and are biomarkers for some diseases in the organs. Although an increasing number of studies have been performed regarding keratins, the roles of keratin in the intestine have not yet been fully understood. This review focuses on discussing the roles of keratins in the intestine. Diverse studies utilizing mouse models and samples from patients with intestinal diseases in the search for the association of keratin in intestinal diseases have been summarized.

Summary: Keratin 8 and 18 (K8/K18) are major intermediate filament proteins of liver hepatocytes. They provide mechanical and nonmechanical stability, thereby protecting cells from stress. Hence, K8-null mice are highly sensitive to Fas-mediated liver cell apoptosis. However, the role of c-Flip protein in K8-null related susceptibility to liver injury is controversial. Here we analyzed c-Flip protein expression in various K8 or K18 null/mutant transgenic livers and show that they are similar in all analyzed transgenic livers and that previously reported c-Flip protein changes are due to antibody cross-reaction with mouse K18. Furthermore, analysis of various apoptosis- or cell survival-related proteins demonstrated that inhibition of phosphorylation of NF-κB and various stress activated protein kinases (SAPKs), such as p38 MAPK, p44/42 MAPK and JNK1/2, is related to the higher sensitivity of K8-null hepatocytes whose nuclear NF-κB is rapidly depleted through Fas-mediated apoptosis. Notably, we found that NF-κB and the studied protein kinases are associated with the K8/K18 complex and are released upon phosphorylation. Therefore, interaction of keratins with cell survival-related protein kinases and transcription factors is another important factor for hepatocyte survival.