ARC is a critical protector against inflammatory bowel disease (IBD) and IBD-associated colorectal tumorigenesis

Qiushi Wang, Tianshun Zhang, Xiaoyu Chang, Do Young Lim, Keke Wang, Ruihua Bai, Ting Wang, Joohyun Ryu, Hanyong Chen, Ke Yao, Wei Ya Ma, Lisa A. Boardman, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

Abstract

The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-kB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/ DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-kB activation in T cells.

Original languageEnglish (US)
Pages (from-to)4158-4171
Number of pages14
JournalCancer Research
Volume80
Issue number19
DOIs
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
The authors thank Todd Schuster for supporting experiments and Tara Adams for supporting animal experiments (The Hormel Institute, University of Minnesota, Austin, MN). This work was supported by the Hormel Foundation (to Z. Dong). This work was also supported by the Clinical Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567).

Funding Information:
The authors thank Todd Schuster for supporting experiments and Tara Adams for supporting animal experiments (The Hormel Institute, University of Minnesota, Austin, MN). This work was supported by the Hormel Foundation (to Z. Dong). This work was also supported by the Clinical Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
© 2020 American Association for Cancer Research.

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