Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Habtezion A, Toivola DM, Asghar MN, Kronmal GS, Brooks JD, Butcher EC, Omary MB
Publisher: NATL ACAD SCIENCES
Publication year: 2011
Journal: Proceedings of the National Academy of Sciences
Journal acronym: P NATL ACAD SCI USA
Volume number: 108
Issue number: 4
Start page: 1445
End page: 1450
Number of pages: 6
ISSN: 0027-8424


Abstract

Keratin 8 (K8) is a major intermediate filament protein present in enterocytes and serves an antiapoptotic function in hepatocytes. K8-null mice develop colonic hyperplasia and colitis that are reversed after antibiotic treatment. To investigate the pathways that underlie the mechanism of colonocyte hyperplasia and the normalization of the colonic phenotype in response to antibiotics, we performed genome-wide microarray analysis. Functional annotation of genes that are differentially regulated in K8(-/-) and K8(+/+) isolated colon crypts (colonocytes) identified apoptosis as a major altered pathway. Exposure of K8(-/-) colonocytes or colon organ ("organoid") cultures, but not K8(-/-) small intestine organoid cultures, to apoptotic stimuli showed, surprisingly, that they are resistant to apoptosis compared with their wild-type counterparts. This resistance is not related to inflammation per se because T-cell receptor alpha-null (TCR-alpha(-/-)) and wild-type colon cultures respond similarly upon induction of apoptosis. Following antibiotic treatment, K8(-/-) colonocytes and organ cultures become less resistant to apoptosis and respond similarly to the wild-type colonocytes. Antibiotics also normalize most differentially up-regulated genes, including survivin and beta 4-integrin. Treatment of K8(-/-) mice with anti-beta 4-integrin antibody up-regulated survivin, and induced phosphorylation of focal adhesion kinase with decreased activation of caspases. Therefore, unlike the proapoptotic effect of K8 mutation or absence in hepatocytes, lack of K8 confers resistance to colonocyte apoptosis in a microflora-dependent manner.

Last updated on 2019-19-06 at 05:49