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Contributed by Richard A. Flavell, December 2, 2020 (sent for review August 21, 2020; reviewed by Lora V. Hooper, Hailiang Huang, and Zhiqiang Zhang)
Significance
RNA helicases play critical roles in multiple biological processes. However, little in vivo data are available because of the lethality of mice completely deficient in RNA helicases. Here, we generate mice with conditional knockout of DEAD-box Helicase 15 (Dhx15) in the intestine, in which we found a specific defect in antimicrobial peptide (AMP) α-defensins in Paneth cells. Additionally, we found that Dhx15-specific depletion in the intestine leads to susceptibility to enteric bacterial infection as well as dextran sulfate sodium-induced colitis in mice. In humans, we also found reduced protein levels of Dhx15 in ulcerative colitis patients.
Abstract
RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15ΔIEC). These mice are susceptible to infection with enteric bacteria Citrobacter rodentium (C. rod), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15ΔIEC mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.
- DEAD-box helicase 15 (Dhx15)
- alpha-defensins
- Paneth cells
- intestinal inflammation
- inflammatory bowel diseases (IBD)
Footnotes
↵1Y.W., K.H., and B.S. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: hwbyang{at}126.com, huabing.li{at}shsmu.edu.cn, richard.flavell{at}yale.edu, or zhushu{at}ustc.edu.cn.
Author contributions: Y.W., K.H., B.S., X.L., H.B.-L., and S.Z. designed research; Y.W., K.H., B.S., X.L., Z.W., R.F., A.W., S.B., Z.Z., M.L., N.H., C.Y., and S.Z. performed research; Y.T., J.W., K.Z., L.L., and H.Y. contributed new reagents/analytic tools; Y.W., K.H., B.S., X.L., W.T., X.Z., Y.T., R.A.F., and S.Z. analyzed data; K.H. and S.Z. wrote the paper; and R.A.F. and S.Z. supervised the research.
Reviewers: L.V.H., University of Texas Southwestern Medical Center; H.H., Broad Institute of Harvard and MIT; and Z.Z., Weill Cornell Medical College.
Competing interest statement: R.F. is a cofounder of Ventus, which studies inflammatory pathways.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2017432118/-/DCSupplemental.
Data Availability Statement.
The data that support the findings of this study are available from the corresponding author upon reasonable request. RNA-seq datasets have been deposited in Gene Expression Omnibus (Bioproject no. PRJNA684445).
Published under the PNAS license.
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The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells
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- Immunology and Inflammation
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