Nutrient Sensing by the Intestinal Epithelium Orchestrates Mucosal Antimicrobial Defense via Translational Control of Hes1.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101302316 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1934-6069 (Electronic) Linking ISSN: 19313128 NLM ISO Abbreviation: Cell Host Microbe Subsets: MEDLINE
    • Publication Information:
      Original Publication: Cambridge, Mass. : Cell Press
    • Subject Terms:
      Gene Expression Regulation* ; Immunity, Mucosal*; Epithelial Cells/*immunology ; Matrix Metalloproteinase 7/*biosynthesis ; Nutrients/*metabolism ; Transcription Factor HES-1/*metabolism ; alpha-Defensins/*biosynthesis; Animals ; Cell Line ; Epithelial Cells/drug effects ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/immunology ; Mice, Inbred C57BL
    • Abstract:
      Metabolic programs and host defense are highly integrated to ensure proper immune responses during stress. Central to these responses, mTOR regulates immune functions by sensing and integrating environmental cues, yet how these systems are coordinated at the intestinal surface remains undefined. We show that the antimicrobial peptide α-defensin is functionally sustained during nutrient deprivation because of regulation of the defensin-processing enzyme MMP7 by microbiota- and host-derived factors. Unlike other antimicrobial peptides, the MMP7-α-defensin axis remains active during nutrient fluctuations, providing essential protection against enteric pathogens. Sustained Mmp7 expression requires the microbiota and is mediated by de-repression of the transcription activator Atoh1 upon attenuation of the transcriptional repressor Hes1 in intestinal epithelial cells. Hes1 levels are regulated via mTOR and controlled translationally, constituting a metabolism-translation-transcription loop. Disrupting this loop by supplying nutrients paradoxically compromises antibacterial defense. Together, these results uncover a regulatory circuit that couples host nutrient status to epithelial antimicrobial immunity.
      (Copyright © 2019 Elsevier Inc. All rights reserved.)
    • Comments:
      Comment in: Cell Host Microbe. 2019 May 8;25(5):632-634. (PMID: 31071290)
    • Contributed Indexing:
      Keywords: Hes1; antimicrobial proteins; enteric infection; intestinal epithelial cell; nutrient sensing; α-defensins
    • Accession Number:
      0 (Hes1 protein, mouse)
      0 (Transcription Factor HES-1)
      0 (alpha-Defensins)
      EC 3.4.24.23 (MMP7 protein, human)
      EC 3.4.24.23 (Matrix Metalloproteinase 7)
    • Publication Date:
      Date Created: 20190505 Date Completed: 20191125 Latest Revision: 20200930
    • Publication Date:
      20231215
    • Accession Number:
      10.1016/j.chom.2019.03.012
    • Accession Number:
      31053533