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TRIM40 is a pathogenic driver of inflammatory bowel disease subverting intestinal barrier integrity

Authors
 Sujin Kang  ;  Jaekyung Kim  ;  Areum Park  ;  Minsoo Koh  ;  Wonji Shin  ;  Gayoung Park  ;  Taeyun A Lee  ;  Hyung Jin Kim  ;  Heonjong Han  ;  Yongbo Kim  ;  Myung Kyung Choi  ;  Jae Hyung Park  ;  Eunhye Lee  ;  Hyun-Soo Cho  ;  Hyun Woo Park  ;  Jae Hee Cheon  ;  Sungwook Lee  ;  Boyoun Park  
Citation
 NATURE COMMUNICATIONS, Vol.14(1) : 700, 2023-02 
Journal Title
NATURE COMMUNICATIONS
Issue Date
2023-02
MeSH
Actins / metabolism ; Animals ; Colitis* / chemically induced ; Colitis* / genetics ; Colitis* / metabolism ; Dextran Sulfate / toxicity ; Disease Models, Animal ; Humans ; Inflammatory Bowel Diseases* / pathology ; Intestinal Mucosa / metabolism ; Intestines ; Male ; Mice ; Mice, Inbred C57BL ; Tripartite Motif Proteins* / genetics ; Tripartite Motif Proteins* / metabolism
Abstract
The cortical actin cytoskeleton plays a critical role in maintaining intestinal epithelial integrity, and the loss of this architecture leads to chronic inflammation, as seen in inflammatory bowel disease (IBD). However, the exact mechanisms underlying aberrant actin remodeling in pathological states remain largely unknown. Here, we show that a subset of patients with IBD exhibits substantially higher levels of tripartite motif-containing protein 40 (TRIM40), a gene that is hardly detectable in healthy individuals. TRIM40 is an E3 ligase that directly targets Rho-associated coiled-coil-containing protein kinase 1 (ROCK1), an essential kinase involved in promoting cell-cell junctions, markedly decreasing the phosphorylation of key signaling factors critical for cortical actin formation and stabilization. This causes failure of the epithelial barrier function, thereby promoting a long-lived inflammatory response. A mutant TRIM40 lacking the RING, B-box, or C-terminal domains has impaired ability to accelerate ROCK1 degradation-driven cortical actin disruption. Accordingly, Trim40-deficient male mice are highly resistant to dextran sulfate sodium (DSS)-induced colitis. Our findings highlight that aberrant upregulation of TRIM40, which is epigenetically silenced under healthy conditions, drives IBD by subverting cortical actin formation and exacerbating epithelial barrier dysfunction.
Files in This Item:
T202300845.pdf Download
DOI
10.1038/s41467-023-36424-0
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/193574
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