Abstract
Cytoplasmic intermediate filaments (IFs) represent a major cytoskeletal network contributing to cell shape, adhesion and migration as well as to tissue resilience and renewal in numerous bilaterians, including mammals. The observation that IFs are dispensable in cultured mammalian cells, but cause tissue-specific, life-threatening disorders, has pushed the need to investigate their function in vivo. In keeping with human disease, the deletion or mutation of murine IF genes resulted in highly specific pathologies. Epidermal keratins, together with desmin, are essential to protect corresponding tissues against mechanical force but also participate in stabilizing cell adhesion and in inflammatory signalling. Surprisingly, other IF proteins contribute to tissue integrity to a much lesser extent than anticipated, pointing towards their role in stress situations. In support, the overexpression of small chaperones or the interference with inflammatory signalling in several settings has been shown to rescue severe tissue pathologies that resulted from the expression of mutant IF proteins. It stills remains an open issue whether the wide range of IF disorders share similar pathomechanisms. Moreover, we lack an understanding how IF proteins participate in signalling processes. Now, with a large number of mouse models in hand, the next challenge will be to develop organotypic cell culture models to dissect pathomechanisms at the molecular level, to employ Crispr/Cas-mediated genome engineering to optimize models and, finally, to combine available animal models with medicinal chemistry for the development of molecular therapies.
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- AMP:
-
adenosine monophosphate
- ATP:
-
adenosine triphosphate
- AxD:
-
Alexander disease
- BCC:
-
basal cell carcinoma
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- DAMPs:
-
danger-associated molecular patterns
- E:
-
embryonic day
- EBS:
-
epidermolysis bullosa simplex
- EGFP:
-
enhanced green fluorescent protein
- GFAP:
-
glial fibrillary acidic protein
- GLUT:
-
glucose transporter
- IF:
-
intermediate filament
- IFN:
-
interferon
- IL-:
-
interleukin-
- K:
-
keratin
- KI:
-
knock in
- KO:
-
knock out
- KtyI:
-
keratin type I
- KtyII:
-
keratin type II
- MDBs:
-
Mallory-Denk bodies
- MECD:
-
Meesmann epithelial corneal dystrophy
- MHC:
-
major histocompatibility complex
- NF-:
-
neurofilament-
- NF-κB:
-
nuclear factor-kappa B
- ROS:
-
reactive oxygen species
- Tg:
-
transgenic
- TNF:
-
tumour necrosis factor
- TNFR:
-
tumour necrosis factor receptor
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- TSLP:
-
thymic stromal lymphopoietin
- WT:
-
wild type
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Acknowledgments
Work in the Magin lab is supported by the DFG (MA1316-15, MA1316-17, MA1316-19, MA1316-21, INST 268/230-1). The authors declare no competing financial interests. For the figure, some illustrations were taken from somersault18:24 website (license: Attribution-NonCommercial-ShareAlike 4.0 International, CC BY-NC-SA 4.0).
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Bouameur, JE., Magin, T.M. (2017). Lessons from Animal Models of Cytoplasmic Intermediate Filament Proteins. In: Parry, D., Squire, J. (eds) Fibrous Proteins: Structures and Mechanisms. Subcellular Biochemistry, vol 82. Springer, Cham. https://doi.org/10.1007/978-3-319-49674-0_7
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