ARC Is a Critical Protector against Inflammatory Bowel Disease (IBD) and IBD-Associated Colorectal Tumorigenesis.

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-κB 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-κB activation in T cells. SIGNIFICANCE: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 19 Pg. 4158-4171 (10 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32816906 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Apoptosis Regulatory Proteins
• CCL5 protein, human
• CXCL5 protein, human
• Chemokine CCL5
• Chemokine CXCL5
• Intracellular Signaling Peptides and Proteins
• Muscle Proteins
• NOL3 protein, human
• Nol3 protein, mouse
• Tifab protein, human
• Dextran Sulfate
• Azoxymethane

Topics

• Animals
• Apoptosis Regulatory Proteins (chemistry, genetics, metabolism)
• Azoxymethane (toxicity)
• Bone Marrow Transplantation
• CD4-Positive T-Lymphocytes (immunology)
• Chemokine CCL5 (metabolism)
• Chemokine CXCL5 (metabolism)
• Colitis (chemically induced)
• Colorectal Neoplasms (chemically induced, etiology)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Female
• Humans
• Inflammatory Bowel Diseases (metabolism, pathology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Jurkat Cells
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle Proteins (chemistry, genetics, metabolism)
• Ubiquitination