Cytoplasmic keratins couple with and maintain nuclear envelope integrity in colonic epithelial cells

Carl Gustaf A. Stenvall, Joel H. Nyström, Ciarán Butler-Hallissey, Theresia Jansson, Taina R.H. Heikkilä, Stephen A. Adam, Roland Foisner, Robert D. Goldman, Karen M. Ridge, Diana M. Toivola*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Keratin intermediate filaments convey mechanical stability and protection against stress to epithelial cells. Keratins are essential for colon health, as seen in keratin 8 knockout (K8−/−) mice exhibiting a colitis phenotype. We hypothesized that keratins support the nuclear envelope and lamina in colonocytes. K8−/− colonocytes in vivo exhibit significantly decreased levels of lamins A/C, B1, and B2 in a colon-specific and cell-intrinsic manner. CRISPR/Cas9- or siRNA-mediated K8 knockdown in Caco-2 cells similarly decreased lamin levels, which recovered after reexpression of K8 following siRNA treatment. Nuclear area was not decreased, and roundness was only marginally increased in cells without K8. Down-regulation of K8 in adult K8flox/flox;Villin-CreERt2 mice following tamoxifen administration significantly decreased lamin levels at day 4 when K8 levels had reduced to 40%. K8 loss also led to reduced levels of plectin, LINC complex, and lamin-associated proteins. While keratins were not seen in the nucleoplasm without or with leptomycin B treatment, keratins were found intimately located at the nuclear envelope and complexed with SUN2 and lamin A. Furthermore, K8 loss in Caco-2 cells compromised nuclear membrane integrity basally and after shear stress. In conclusion, colonocyte K8 helps maintain nuclear envelope and lamina composition and contributes to nuclear integrity.

Original languageEnglish (US)
JournalMolecular biology of the cell
Volume33
Issue number13
DOIs
StatePublished - Nov 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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