Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)

Interna författare/redaktörer

Publikationens författare: Lähdeniemi IAK, Misiorek JO, Antila CJM, Landor S, Stenvall C-G, Fortelius LE, Bergström LK, Sahlgren C & Toivola DM
Förläggare: Nature Publishing Group
Publiceringsår: 2017
Tidskrift: Cell Death and Differentiation
Volym: 24
Nummer: 6
Artikelns första sida, sidnummer: 984
Artikelns sista sida, sidnummer: 996
eISSN: 1476-5403


Keratins (K) are intermediate filament proteins important in stress
protection and mechanical support of epithelial tissues. K8, K18 and K19
are the main colonic keratins, and K8-knockout (K8−/−) mice
display a keratin dose-dependent hyperproliferation of colonic crypts
and a colitis-phenotype. However, the impact of the loss of K8 on
intestinal cell differentiation has so far been unknown. Here we show
that K8 regulates Notch1 signalling activity and differentiation in the
epithelium of the large intestine. Proximity ligation and
immunoprecipitation assays demonstrate that K8 and Notch1 co-localize
and interact in cell cultures, and in vivo in the colonic
epithelial cells. K8 with its heteropolymeric partner K18 enhance Notch1
protein levels and activity in a dose dependent manner. The levels of
the full-length Notch1 receptor (FLN), the Notch1 intracellular domain
(NICD) and expression of Notch1 downstream target genes are reduced in
the absence of K8, and the K8-dependent loss of Notch1 activity can be
rescued with re-expression of K8/K18 in K8-knockout CRISPR/Cas9 Caco-2
cells protein levels. In vivo, K8 deletion with subsequent
Notch1 downregulation leads to a shift in differentiation towards a
goblet cell and enteroendocrine phenotype from an enterocyte cell fate.
Furthermore, the K8−/− colonic hyperproliferation results
from an increased number of transit amplifying progenitor cells in these
mice. K8/K18 thus interact with Notch1 and regulate Notch1 signalling
activity during differentiation of the colonic epithelium.

Senast uppdaterad 2020-26-05 vid 05:25