Abstract
Keratin (K) intermediate filaments can be divided into type I/type II proteins, which form obligate heteropolymers. Epithelial cells express type I-type II keratin pairs, and K7, K8 (type II) and K18, K19 and K20 (type I) are the primary keratins found in the single-layered intestinal epithelium. Keratins are upregulated during stress in liver, pancreas, lung, kidney and skin, however, little is known about their dynamics in the intestinal stress response. Here, keratin mRNA, protein and phosphorylation levels were studied in response to murine colonic stresses modeling human conditions, and in colorectal cancer HT29 cells. Dextran sulphate sodium (DSS)-colitis was used as a model for intestinal inflammatory stress, which elicited a strong upregulation and widened crypt distribution of K7 and K20. K8 levels were slightly downregulated in acute DSS, while stress-responsive K8 serine-74 phosphorylation (K8 pS74) was increased. By eliminating colonic microflora using antibiotics, K8 pS74 in proliferating cells was significantly increased, together with an upregulation of K8 and K19. In the aging mouse colon, most colonic keratins were upregulated. In vitro, K8, K19 and K8 pS74 levels were increased in response to lipopolysaccharide (LPS)-induced inflammation in HT29 cells. In conclusion, intestinal keratins are differentially and dynamically upregulated and post-translationally modified during stress and recovery.
Highlights
Keratin (K) intermediate filaments (IF) are cytoskeletal proteins that protect the cell from mechanical and non-mechanical stress [1]
In order to define if keratin levels are altered in an acute model of colitis, protein and mRNA
We find that K7 and K20 are stress-responsive keratin upregulated in the three colitis regimen used, while the main colonic keratins K8 and K19 are increased in response to oral antibiotic-treatment
Summary
Keratin (K) intermediate filaments (IF) are cytoskeletal proteins that protect the cell from mechanical and non-mechanical stress [1]. The most common simple epithelial keratins (SEK) are K7, K8, K18, K19 and K20, and they are divided into acidic type I (K18-K20) and basic type II (K7-K8). Type I and type II keratins form non-covalent obligate heteropolymers in a 1:1 ratio, and they are expressed in specific pairs and in a tissue-specific manner [2]. K18 are expressed in hepatocytes, whereas all SEKs are found in intestinal epithelia [3]. Keratins are regulated by posttranslational modifications (PTM), and phosphorylation is the most common and best described PTM [4]. Serine 74 (S74) is the major amino acid on K8 that is phosphorylated during stress, apoptosis and mitosis [4].
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