title: Loss of TMF/ARA160 protein renders colonic mucus refractory to bacterial colonization and diminishes intestinal susceptibility to acute colitis.
abstract: TMF/ARA160 is a Golgi-associated protein with several cellular functions, among them direction of the NF-κB subunit, p65 RelA, to ubiquitination and proteasomal degradation in stressed cells. We sought to investigate the role of TMF/ARA160 under imposed stress conditions in vivo. TMF(-/-) and wild-type (WT) mice were treated with the ulcerative agent dextran sulfate sodium (DSS), and the severity of the inflicted acute colitis was determined. TMF(-/-) mice were found to be significantly less susceptible to DSS-induced colitis, with profoundly less bacterial penetration into the colonic epithelia. Surprisingly, unlike in WT mice, no bacterial colonies were visualized in colons of healthy untreated TMF(-/-) mice, indicating the constitutive resistance of TMF(-/-) colonic mucus to bacterial retention and penetration. Gene expression analysis of colon tissues from unchallenged TMF(-/-) mice revealed 5-fold elevated transcription of the muc2 gene, which encodes the major component of the colonic mucus gel, the MUC2 mucin. Accordingly, the morphology of the colonic mucus in TMF(-/-) mice was found to differ from the mucus structure in WT colons. The NF-κB subunit, p65, a well known transcription inducer of muc2, was up-regulated significantly in TMF(-/-) intestinal epithelial cells. However, this did not cause spontaneous inflammation or increased colonic crypt cell proliferation. Collectively, our findings demonstrate that absence of TMF/ARA160 renders the colonic mucus refractory to bacterial colonization and the large intestine less susceptible to the onset of colitis.
authors.affiliation: The Mina and Everard Goodman Faculty of Life-Science, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Bel
authors.forename: Yoav
authors.initials: Y
authors.lastname: Elkis
authors.forename: Tali
authors.initials: T
authors.lastname: Lerer-Goldstein
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Sally
authors.initials: S
authors.lastname: Shpungin
authors.forename: Uri
authors.initials: U
authors.lastname: Nir
mesh_terms: D000818:Animals; D001419:Bacteria; D018988:Bacterial Translocation / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004268:DNA-Binding Proteins; D016264:Dextran Sulfate / Q000633:toxicity; D000077614:Golgi Matrix Proteins; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000077614:Golgi Matrix Proteins; C524626:Muc2 protein, mouse; D055262:Mucin-2; C498144:Rela protein, mouse; C554202:Tmf1 protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D016264:Dextran Sulfate; D044767:Ubiquitin-Protein Ligases