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An isoform of ZBP-89 predisposes the colon to colitis.

ABSTRACT: Alternative splicing enables expression of functionally diverse protein isoforms. The structural and functional complexity of zinc-finger transcription factor ZBP-89 suggests that it may be among the class of alternatively spliced genes. We identified a human ZBP-89 splice isoform (ZBP-89(DeltaN)), which lacks amino terminal residues 1-127 of the full-length protein (ZBP-89(FL)). ZBP-89(DeltaN) mRNA was co-expressed with its ZBP-89(FL) cognate in gastrointestinal cell lines and tissues. Similarly, ZBP-89(DeltaN) protein was expressed. To define its function in vivo, we generated ZBP-89(DeltaN) knock-in mice by targeting exon 4 that encodes the amino terminus. Homozygous ZBP-89(DeltaN) mice, expressing only ZBP-89(DeltaN) protein, experienced growth delay, reduced viability and increased susceptibility to dextran sodium sulfate colitis. We conclude that ZBP-89(DeltaN) antagonizes ZBP-89(FL) function and that over-expression of the truncated isoform disrupts gastrointestinal homeostasis.

SUBMITTER: Law DJ

PROVIDER: S-EPMC1390687 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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An isoform of ZBP-89 predisposes the colon to colitis.

Law David J DJ Labut Edwin M EM Adams Rachael D RD Merchant Juanita L JL

Nucleic acids research 20060303 5

Alternative splicing enables expression of functionally diverse protein isoforms. The structural and functional complexity of zinc-finger transcription factor ZBP-89 suggests that it may be among the class of alternatively spliced genes. We identified a human ZBP-89 splice isoform (ZBP-89(DeltaN)), which lacks amino terminal residues 1-127 of the full-length protein (ZBP-89(FL)). ZBP-89(DeltaN) mRNA was co-expressed with its ZBP-89(FL) cognate in gastrointestinal cell lines and tissues. Similarl ...[more]

PMID: 16517939

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Project description:ZBP-89 (also ZNF148 or Zfp148) is a butyrate-inducible zinc finger transcription factor that binds to GC-rich DNA elements. Deletion of the N-terminal domain is sufficient to increase mucosal susceptibility to chemical injury and inflammation. We investigated whether conditional deletion of ZBP-89 from the intestinal and colonic epithelium of mice increases their susceptibility to pathogens such as Salmonella typhimurium.We generated mice with a conditional null allele of Zfp148 (ZBP-89(FL/FL)) using homologous recombination to flank Zfp148 with LoxP sites (ZBP-89(FL/FL)), and then bred the resulting mice with those that express VillinCre. We used microarray analysis to compare gene expression patterns in colonic mucosa between ZBP-89(?Int) and C57BL/6 wild-type mice (controls). Mice were gavaged with 2 isogenic strains of S. typhimurium after administration of streptomycin.Microarray analysis revealed that the colonic mucosa of ZBP-89(?Int) mice had reduced levels of tryptophan hydroxylase 1 (Tph1) messenger RNA, encoding the rate-limiting enzyme in enterochromaffin cell serotonin (5-hydroxytryptamine [5HT]) biosynthesis. DNA affinity precipitation demonstrated direct binding of ZBP-89 to the mouse Tph1 promoter, which was required for its basal and butyrate-inducible expression. ZBP-89(?Int) mice did not increase mucosal levels of 5HT in response to S. typhimurium infection, and succumbed to the infection 2 days before control mice. The ?hilA isogenic mutant of S. typhimurium lacks this butyrate-regulated locus and stimulated, rather than suppressed, expression of Tph1 approximately 50-fold in control, but not ZBP-89(?Int), mice, correlating with fecal levels of butyrate.ZBP-89 is required for butyrate-induced expression of the Tph1 gene and subsequent production of 5HT in response to bacterial infection in mice. Reductions in epithelial ZBP-89 increase susceptibility to colitis and sepsis after infection with S. typhimurium, partly because of reduced induction of 5HT production in response to butyrate and decreased secretion of antimicrobial peptides.

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An isoform of ZBP-89 predisposes the colon to colitis.

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An isoform of ZBP-89 predisposes the colon to colitis.

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