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

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 () and Boyoun Park ()
Additional contact information
Sujin Kang: Yonsei University
Jaekyung Kim: Yonsei University
Areum Park: Yonsei University
Minsoo Koh: Yonsei University
Wonji Shin: Yonsei University
Gayoung Park: Yonsei University
Taeyun A. Lee: Yonsei University
Hyung Jin Kim: Yonsei University
Heonjong Han: Yonsei University
Yongbo Kim: Division of Tumor Immunology, Research Institute, National Cancer Center
Myung Kyung Choi: Yonsei University
Jae Hyung Park: Yonsei University
Eunhye Lee: Yonsei University
Hyun-Soo Cho: Yonsei University
Hyun Woo Park: Yonsei University
Jae Hee Cheon: Yonsei University College of Medicine
Sungwook Lee: Division of Tumor Immunology, Research Institute, National Cancer Center
Boyoun Park: Yonsei University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36424-0

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