Type I interferons control proliferation and function of the intestinal epithelium

Yuliya V. Katlinskaya, Kanstantsin V. Katlinski, Audrey Lasri, Ning Li, Daniel P. Beiting, Amy C. Durham, Ting Yang, Eli Pikarsky, Christopher J. Lengner, F. Brad Johnson, Yinon Ben-Neriah, Serge Y. Fuchs*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type I interferons (IFN) produced in the gut under the influence of microbiota are known for their antiproliferative effects, the role of these cytokines in regulating intestinal epithelial cell renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls the ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1α leads to the activation of both β-catenin and IFN pathways and prevents the unlimited proliferation of intestinal epithelial cells despite constitutive β-catenin activity. IFN signaling contributes to the activation of the p53 pathway and the appearance of apoptotic and senescence markers in the CK1α-deficient gut. Concurrent genetic ablation of CK1α and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of barrier function. These data indicate that IFN play an important role in controlling the proliferation and function of the intestinal epithelium in the context of β-catenin activation.

Original languageAmerican English
Pages (from-to)1124-1135
Number of pages12
JournalMolecular and Cellular Biology
Volume36
Issue number7
DOIs
StatePublished - 1 Apr 2016

Bibliographical note

Funding Information:
This work was supported by NIH/NCI grants RO1 CA092900 and PO1 CA165997 (to S.Y.F.), including help from the Scientific Cell/Tissue Morphology Core and its principal investigator, Qian-Chun Yu. We thank D. E. Zhang for reagents and A. Ortiz for help with manuscript preparation. Office of Extramural Research, National Institutes of Health (OER) provided funding to Serge Y. Fuchs under grant number CA165997. Office of Extramural Research, National Institutes of Health (OER) provided funding to Serge Y. Fuchs under grant number CA092900.

Publisher Copyright:
© 2016, American Society for Microbiology.

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