An isoform of ZBP-89 predisposes the colon to colitis

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^δN), which lacks amino terminal residues 1-127 of the full-length protein (ZBP-89 FL). ZBP-89^δN mRNA was co-expressed with its ZBP-89 FL cognate in gastrointestinal cell lines and tissues. Similarly, ZBP-89^δN protein was expressed. To define its function in vivo, we generated ZBP-89^δN knock-in mice by targeting exon 4 that encodes the amino terminus. Homozygous ZBP-89^δN mice, expressing only ZBP-89^δN protein, experienced growth delay, reduced viability and increased susceptibility to dextran sodium sulfate colitis. We conclude that ZBP-89^δN antagonizes ZBP-89 FL function and that over-expression of the truncated isoform disrupts gastrointestinal homeostasis.