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Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti

Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant‐negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a r...

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Autores principales: Renz, Patricia, Imahorn, Elias, Spoerri, Iris, Aushev, Magomet, March, Oliver P., Wariwoda, Hedwig, Von Arb, Sarah, Volz, Andreas, Itin, Peter H., Reichelt, Julia, Burger, Bettina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850952/
https://www.ncbi.nlm.nih.gov/pubmed/31638346
http://dx.doi.org/10.1111/jcmm.14727
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author Renz, Patricia
Imahorn, Elias
Spoerri, Iris
Aushev, Magomet
March, Oliver P.
Wariwoda, Hedwig
Von Arb, Sarah
Volz, Andreas
Itin, Peter H.
Reichelt, Julia
Burger, Bettina
author_facet Renz, Patricia
Imahorn, Elias
Spoerri, Iris
Aushev, Magomet
March, Oliver P.
Wariwoda, Hedwig
Von Arb, Sarah
Volz, Andreas
Itin, Peter H.
Reichelt, Julia
Burger, Bettina
author_sort Renz, Patricia
collection PubMed
description Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant‐negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a result of the altered carboxy (C)‐terminus, from poly‐glycine to either a poly‐arginine or ‐alanine tail. Previous studies on the type of C‐terminus and subcellular localization of the respective mutant protein are divergent. In order to fully elucidate the pathomechanism of IWC, a greater understanding is critical. This study aimed to establish the consequences for localization and intermediate filament formation of altered keratin 10 (K10) C‐termini. To achieve this, plasmids expressing distinct KRT10 variants were generated. Sequences encoded all possible reading frames of the K10 C‐terminus as well as a nonsense variant. A keratinocyte line was transfected with these plasmids. Additionally, gene editing was utilized to introduce frameshift variants in exon 6 and exon 7 at the endogenous KRT10 locus. Cellular localization of aberrant K10 was observed via immunofluorescence using various antibodies. In each setting, immunofluorescence analysis demonstrated aberrant nuclear localization of K10 featuring an arginine‐rich C‐terminus. However, this was not observed with K10 featuring an alanine‐rich C‐terminus. Instead, the protein displayed cytoplasmic localization, consistent with wild‐type and truncated forms of K10. This study demonstrates that, of the various 3′ frameshift variants of KRT10, exclusively arginine‐rich C‐termini lead to nuclear localization of K10.
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spelling pubmed-68509522019-12-01 Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti Renz, Patricia Imahorn, Elias Spoerri, Iris Aushev, Magomet March, Oliver P. Wariwoda, Hedwig Von Arb, Sarah Volz, Andreas Itin, Peter H. Reichelt, Julia Burger, Bettina J Cell Mol Med Original Articles Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant‐negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a result of the altered carboxy (C)‐terminus, from poly‐glycine to either a poly‐arginine or ‐alanine tail. Previous studies on the type of C‐terminus and subcellular localization of the respective mutant protein are divergent. In order to fully elucidate the pathomechanism of IWC, a greater understanding is critical. This study aimed to establish the consequences for localization and intermediate filament formation of altered keratin 10 (K10) C‐termini. To achieve this, plasmids expressing distinct KRT10 variants were generated. Sequences encoded all possible reading frames of the K10 C‐terminus as well as a nonsense variant. A keratinocyte line was transfected with these plasmids. Additionally, gene editing was utilized to introduce frameshift variants in exon 6 and exon 7 at the endogenous KRT10 locus. Cellular localization of aberrant K10 was observed via immunofluorescence using various antibodies. In each setting, immunofluorescence analysis demonstrated aberrant nuclear localization of K10 featuring an arginine‐rich C‐terminus. However, this was not observed with K10 featuring an alanine‐rich C‐terminus. Instead, the protein displayed cytoplasmic localization, consistent with wild‐type and truncated forms of K10. This study demonstrates that, of the various 3′ frameshift variants of KRT10, exclusively arginine‐rich C‐termini lead to nuclear localization of K10. John Wiley and Sons Inc. 2019-10-22 2019-12 /pmc/articles/PMC6850952/ /pubmed/31638346 http://dx.doi.org/10.1111/jcmm.14727 Text en © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Renz, Patricia
Imahorn, Elias
Spoerri, Iris
Aushev, Magomet
March, Oliver P.
Wariwoda, Hedwig
Von Arb, Sarah
Volz, Andreas
Itin, Peter H.
Reichelt, Julia
Burger, Bettina
Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
title Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
title_full Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
title_fullStr Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
title_full_unstemmed Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
title_short Arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
title_sort arginine‐ but not alanine‐rich carboxy‐termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850952/
https://www.ncbi.nlm.nih.gov/pubmed/31638346
http://dx.doi.org/10.1111/jcmm.14727
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