TY - JOUR
T1 - The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells
AU - Wang, Yalong
AU - He, Kaixin
AU - Sheng, Baifa
AU - Lei, Xuqiu
AU - Tao, Wanyin
AU - Zhu, Xiaoliang
AU - Wei, Zheng
AU - Fu, Rongjie
AU - Wang, Anlei
AU - Bai, Shengdan
AU - Zhang, Zhao
AU - Hong, Na
AU - Ye, Chao
AU - Tian, Ye
AU - Wang, Jun
AU - Li, Mingsong
AU - Zhang, Kaiguang
AU - Li, Lin
AU - Yang, Hua
AU - Li, Hua Bing
AU - Flavell, Richard A.
AU - Zhu, Shu
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Xingxing Ren and Runzhi Li for maintaining some of the mouse colonies and Min Huang for plasmid construction. This work was supported by National Key R&D Program of China Grant 2018YFA0508000 (to S.Z.), Strategic Priority Research Program of the Chinese Academy of Sciences Grant XDB29030101 (to S.Z.), National Natural Science Foundation of China Grants 81822021, 91842105, 31770990, 81821001 (to S.Z.), and 91753141/82030042/32070917 (to H.-B.L.), and Fundamental Research Funds for the Central Universities Grants WK2070000159 (to S.Z.). R.A.F. is an Investigator at the Howard Hughes Medical Institute.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/1/26
Y1 - 2021/1/26
N2 - 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.
AB - 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.
KW - Alpha-defensins
KW - DEAD-box helicase 15 (Dhx15)
KW - Inflammatory bowel diseases (IBD)
KW - Intestinal inflammation
KW - Paneth cells
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U2 - 10.1073/pnas.2017432118
DO - 10.1073/pnas.2017432118
M3 - Article
C2 - 33483420
AN - SCOPUS:85100057752
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
M1 - e2017432118
ER -