Keratins modulate colonocyte electrolyte transport via protein mistargeting

@article{Toivola2004KeratinsMC,
  title={Keratins modulate colonocyte electrolyte transport via protein mistargeting},
  author={Diana M. Toivola and Selvi Krishnan and Henry J. Binder and Satish K. Singh and M. Bishr Omary},
  journal={The Journal of Cell Biology},
  year={2004},
  volume={164},
  pages={911 - 921}
}
The function of intestinal keratins is unknown, although keratin 8 (K8)–null mice develop colitis, hyperplasia, diarrhea, and mistarget jejunal apical markers. We quantified the diarrhea in K8-null stool and examined its physiologic basis. Isolated crypt-units from K8-null and wild-type mice have similar viability. K8-null distal colon has normal tight junction permeability and paracellular transport but shows decreased short circuit current and net Na absorption associated with net Cl… 

Figures and Tables from this paper

Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon.
TLDR
The loss of DRA in the K8(-/-) mouse colon and cecum explains the dramatic chloride transport defect and diarrheal phenotype after K8 inactivation and identifies K8 as a novel regulator of D RA.
Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon
TLDR
Functional annotation of genes that are differentially regulated in K8−/− and K8+/+ isolated colon crypts (colonocytes) identified apoptosis as a major altered pathway and lack of K8 confers resistance to colonocyte apoptosis in a microflora-dependent manner.
The Amount of Keratins Matters for Stress Protection of the Colonic Epithelium
TLDR
The K8+/− mild colonic phenotype correlates with decreased keratin levels and increased sensitivity to experimental colitis, suggesting that a sufficient amount of keratin is needed for efficient stress protection in the colonic epithelia.
Keratins Are Altered in Intestinal Disease-Related Stress Responses
TLDR
In conclusion, intestinal keratins are differentially and dynamically upregulated and post-translationally modified during stress and recovery.
Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway
TLDR
It is shown that K8 regulates Notch1 signalling activity and differentiation in the epithelium of the large intestine and can be rescued with re-expression of K8/K18 in K8-knockout CRISPR/Cas9 Caco-2 cells protein levels.
Targeted deletion of keratin 8 in intestinal epithelial cells disrupts tissue integrity and predisposes to tumorigenesis in the colon
TLDR
Intestinal epithelial K8 plays a significant role in colonocyte epithelial integrity maintenance, proliferation regulation and tumor suppression, and induces a dramatically increased sensitivity to azoxymethane-induced tumorigenesis.
The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice
TLDR
It is demonstrated that loss of the intermediate filament network had no significant effect on bile formation and composition, as well as expression levels and membrane targeting of key hepatobiliary transporters under baseline and stress conditions, but loss of K8 significantly increased liver injury in response to toxic stress.
Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells
TLDR
A novel, colonocyte-specific role for K8 in nuclear function is identified and hyperphosphorylation of the lamin A-associated cell cycle regulator pRb in K8−/− colonocytes together with increased nuclear localization of the mechanosensor YAP provide a molecular mechanism for the hyperproliferation phenotype.
Plectin ensures intestinal epithelial integrity and protects colon against colitis
TLDR
It is hypothesized that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis and feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the PleΔIEC colon.
Role of epithelial ion transports in inflammatory bowel disease.
TLDR
This systematic review analyses and integrates the current evidence on the roles of epithelial Na( +)-K(+)-ATPase (NKA), Na(+)/H(+) exchangers (NHEs), epithelialNa(+) channels (ENaC), and K(+ channels (KC) in IBD-associated diarrhea.
...
...

References

SHOWING 1-10 OF 63 REFERENCES
Simple epithelial keratins are dispensable for cytoprotection in two pancreatitis models.
TLDR
Analysis of keratin filaments in pancreata of K8- and K18-null mice shows that absence of total filaments or CF does not increase susceptibility to pancreatitis induced by caerulein or a choline-deficient diet, and acinar keratins appear to be dispensable for cytoprotection.
Electrolyte transport in the mammalian colon: mechanisms and implications for disease.
TLDR
Knowledge of the mechanisms of electrolyte transport in the colon enables the development of new strategies for the treatment of CF and secretory diarrhea and will lead to a better understanding of the pathophysiological events during inflammatory bowel disease and development of colonic carcinoma.
Reduction of cytochemical ecto-ATPase activities in keratin 8-deficient FVB/N mouse livers
TLDR
Results reveal for the first time different microscopical findings regarding the livers of these three genotypes and suggest that the reduction of ecto-ATPase plays a role in the increased fragility of (+/−) and (−/ −) mouse livers.
Renal and intestinal absorptive defects in mice lacking the NHE3 Na +/H+ exchanger
TLDR
Physiological data show that NHE3 is the major absorptive Na+/H+ exchanger in kidney and intestine, and that lack of the exchanger impairs acid-base balance and Na+-fluid volume homeostasis.
Simple epithelium keratins are required for maintenance of hepatocyte integrity.
TLDR
It is demonstrated that simple epithelium keratins are essential for the maintenance of hepatocyte structural and functional integrity and are caused by the disruption of the K8 gene.
Disturbances in hepatic cell‐cycle regulation in mice with assembly‐deficient keratins 8/18
TLDR
Results indicate that absence of keratin filaments causes disturbances in cell‐cycle regulation, driving cells into the S‐G2 phase and causing aberrant cytokinesis, which could stem from disturbed functions of K8/18‐dependent cell‐ cycle regulators, such as the signaling integrator, 14‐3‐3.
Keratin 20 helps maintain intermediate filament organization in intestinal epithelia.
TLDR
Cross-breeding of wild-type or R80H K20 mice with mice that overexpress wild- type K18 or K18 that is mutated at the conserved K20 Arg80-equivalent residue show that K20 plays an additive and compensatory role with K18 in maintaining keratin filament organization in the intestine.
Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation
TLDR
It is reported that K8-null mouse hepatocytes in primary culture and in vivo are three- to fourfold more sensitive to Fas-mediated apoptosis after stimulation with Jo2, an agonistic antibody of Fas ligand.
Colonic H-K-ATPase β-subunit: identification in apical membranes and regulation by dietary K depletion.
TLDR
Tissue-specific upregulation of this β-subunit mRNA in response to K depletion, localization of its protein, its upregulation by K depletion in apical membranes of distal colon, and its physical association with HKcα protein provide compelling evidence that HKcβ is the putative β- subunit of colonic H-K-ATPase.
...
...