Analysis of Keratin Polypeptides 8 and 19 Variants in Inflammatory Bowel Disease

Tao, Guo–Zhong; Strnad, Pavel; Zhou, Qin; Kamal, Ahmad; Zhang, Leilei; Madani, Nahid D.; Kugathasan, Subra; Brant, Steven R.; Cho, Judy H.; Omary, M. Bishr; Duerr, Richard H.

doi:10.1016/j.cgh.2007.02.017

Cited by 38 publications

(44 citation statements)

References 40 publications

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“…86, 87). Although K8 variants were noted in some patients with IBD (88), an assessment of a large cohort of patients, primarily with familial IBD, did not provide a strong association (87). In addition, there is no evidence of SEK variant association with human pancreatitis based on analysis of 2 large cohorts of patients (89,90) and further supported by transgenic mouse studies (20,76,79).…”

Section: See How Clinical and Experimental Observations Lead To Undermentioning

confidence: 96%

Toward unraveling the complexity of simple epithelial keratins in human disease

Omary¹,

Ku²,

Strnad³

et al. 2009

J. Clin. Invest.

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Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18-K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease.

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Section: See How Clinical and Experimental Observations Lead To Undermentioning

confidence: 96%

Toward unraveling the complexity of simple epithelial keratins in human disease

Omary¹,

Ku²,

Strnad³

et al. 2009

J. Clin. Invest.

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240

357

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“…To date, three of these have been described (Fig. 8A) (Ku et al, 2001;Ku et al, 2005;Tao et al, 2007) and were shown biochemically to lead to disulphide bridge formation (Ku et al, 2001;Ku et al, 2005;Tao et al, 2007), thereby limiting the ability of K8/K18 filaments to reorganize in Fig. 4.…”

Section: Discussionmentioning

confidence: 99%

Unique amino acid signatures that are evolutionarily conserved distinguish simple-type, epidermal and hair keratins

Strnad

Usachov

Debès

et al. 2011

Journal of Cell Science

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SummaryKeratins (Ks) consist of central a-helical rod domains that are flanked by non-a-helical head and tail domains. The cellular abundance of keratins, coupled with their selective cell expression patterns, suggests that they diversified to fulfill tissue-specific functions although the primary structure differences between them have not been comprehensively compared. We analyzed keratin sequences from many species: K1, K2, K5, K9, K10, K14 were studied as representatives of epidermal keratins, and compared with K7, K8, K18, K19, K20 and K31, K35, K81, K85, K86, which represent simple-type (single-layered or glandular) epithelial and hair keratins, respectively. We show that keratin domains have striking differences in their amino acids. There are many cysteines in hair keratins but only a small number in epidermal keratins and rare or none in simple-type keratins. The heads and/or tails of epidermal keratins are glycine and phenylalanine rich but alanine poor, whereas parallel domains of hair keratins are abundant in prolines, and those of simple-type epithelial keratins are enriched in acidic and/or basic residues. The observed differences between simple-type, epidermal and hair keratins are highly conserved throughout evolution. Cysteines and histidines, which are infrequent keratin amino acids, are involved in de novo mutations that are markedly overrepresented in keratins. Hence, keratins have evolutionarily conserved and domain-selectively enriched amino acids including glycine and phenylalanine (epidermal), cysteine and proline (hair), and basic and acidic (simple-type epithelial), which reflect unique functions related to structural flexibility, rigidity and solubility, respectively. Our findings also support the importance of human keratin 'mutation hotspot' residues and their wild-type counterparts.

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“…Liver keratins serve as stress markers by increasing their expression up to 3-fold, akin to heat shock protein (hsp)-70 which they bind to, 3 and by undergoing posttranslational modifications such as phosphorylation, caspase-mediated fragmentation, ubiquitination and cross-linking. 7,17 Dynamic increased/decreased keratin 12 Tao et al, 63 Schneider et al 65 Europe** 37/2255 (1.6%) 88/6061 (1.5%) Ͼ0.5 1.1 (0.8-1.7) Strnad et al, 14 Treiber et al, 16 Halangk et al, 59 , Schoniger-Hekele et al, 60 Strnad et al, 62 Owens et al, 64 Buning et al, 66 Cavestro et al 67 site-specific phosphorylation serve as reliable markers for human liver disease progression/regression, 18 and for epithelial cell injury in general. 7 The keratin-related genetic animal models 3,7,19,20 and ex vivo cell culture studies 20,21 demonstrated the importance of keratins in protecting hepatocytes from oxidative and other hepatotoxic injuries that promote apoptosis, and also highlighted several important keratin functions (Fig.…”

Section: Hepatocyte Keratin Functions and Their Modulation By Keratinmentioning

confidence: 99%

Keratins let liver live: Mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies

et al. 2007

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Keratin polypeptides 8 and 18 (K8/K18) are the cytoskeletal intermediate filament proteins of hepatocytes while K8/K18/K19 are the keratins of hepatobiliary ductal cells. Hepatocyte K8/K18 are highly abundant and behave as stress proteins with injury-inducible expression. Human association studies show that K8/K18 germline heterozygous mutations predispose to end-stage liver disease of multiple etiologies (Ϸ3 fold increased risk), and to liver disease progression in patients with chronic hepatitis C infection. These findings are supported by extensive transgenic mouse and ex vivo primary hepatocyte culture studies showing that K8 or K18 mutations predispose the liver to acute or subacute injury and promote apoptosis and fibrosis. Mutation-associated predisposition to liver injury is likely related to mechanical and nonmechanical keratin functions including maintenance of cell integrity, protection from apoptosis and oxidative injury, serving as a phosphate sponge, regulation of mitochondrial organization/function and protein targeting. These functions are altered by mutationinduced changes in keratin phosphorylation, solubility and filament organization/reorganization. Keratins are also the major constituents of Mallory-Denk bodies (MDBs). A toxin-induced K8>K18 ratio, and keratin crosslinking by transglutaminase-2 play essential roles in MDB formation. Furthermore, intracellular or cell-released K18 fragments, generated by caspase-mediated proteolysis during apoptosis serve as markers of liver injury. Therefore, K8 and K18 are cytoprotective stress proteins that play a central role in guarding hepatocytes from apoptosis. Keratin involvement in liver disease is multi-faceted and includes modulating disease progression upon mutation, formation of MDBs in response to unique forms of injury, and serving as markers of epithelial cell death. (HEPATOLOGY 2007; 46:1639-1649.)

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Analysis of Keratin Polypeptides 8 and 19 Variants in Inflammatory Bowel Disease

Cited by 38 publications

References 40 publications

Toward unraveling the complexity of simple epithelial keratins in human disease

Toward unraveling the complexity of simple epithelial keratins in human disease

Unique amino acid signatures that are evolutionarily conserved distinguish simple-type, epidermal and hair keratins

Keratins let liver live: Mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies

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