AGR2-mediated cell-cell communication controls the antiviral immune response by promoting the thiol oxidation of TRAF3

• Published in: Redox biology Vol. 82; p. 103581
• Main Authors: Jia, Mengqi, Chen, Xiaojing, Guo, Wenxue, Ma, Dapeng, Wang, Peng, Niu, Huanmin, Liu, Changhong, Lin, Xianjuan, Lu, QiQi, Wang, Jing, Zheng, Xiaoxue, Sun, Qi, Gao, Chengjiang, Yuan, Huiqing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2025; Elsevier
• Subjects: AGR2; Animals; Disulfide bond; HEK293 Cells; Humans; Interferon Type I - metabolism; Macrophages - immunology; Macrophages - metabolism; Mice; Mucoproteins - genetics; Mucoproteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidation-Reduction; Protein disulfide isomerases; Research Paper; Sulfhydryl Compounds - metabolism; TNF Receptor-Associated Factor 3 - chemistry; TNF Receptor-Associated Factor 3 - genetics; TNF Receptor-Associated Factor 3 - metabolism; TRAF3; Type I interferon; AGR2; Type I interferon; Disulfide bond; TRAF3; Protein disulfide isomerases
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2025.103581

Protein disulfide isomerases (PDIs) are essential catalysts for the formation and isomerization of disulfide bonds in diverse substrate proteins and exert multiple functions under pathophysiological conditions. Here, we show that anterior gradient 2 (AGR2), a member of PDIs, acts as a negative regulator in antiviral immunity. RNA virus infection stimulated the expression and secretion of AGR2 in epithelial cells. While AGR2 is absent in immune cells, both intracellular AGR2 and extracellular AGR2 compromised type I interferon (IFN–I) production in vitro and in vivo. The inhibitory effect of secreted AGR2 on the immune response resulted from its crosstalk with immune cells, such as macrophages, by which eAGR2 was internalized via endocytosis depending on its adhesion motif. We further identified AGR2 as a novel binding protein of TRAF3, which forms a disulfide bond between Cys81 of AGR2 and Cys296 on TRAF3. This interaction led to the inhibition of TRAF3 K63-linked ubiquitination and TRAF3-TBK1 complex formation, ultimately impairing TRAF3's ability to induce IFN-I production. The TRAF3 Cys296 mutation diminishes oxidative modification by AGR2 but enhances self-association of TRAF3 and IFN-I production. Our study demonstrated a cysteine-dependent oxidative modification of TRAF3 by AGR2 that suppresses TRAF3 activity and maintains innate immune homeostasis. [Display omitted] •AGR2 impairs type I interferon production during RNA virus infection in epithelial cells.•AGR2 is deficient in macrophages, but internalization of extracellular AGR2 inhibits antiviral innate immunity in macrophages.•AGR2 acts as a novel binding protein for TRAF3 by forming a disulfide bond between Cys81 on AGR2 and Cys296 on TRAF3.•The TRAF3 Cys296 mutation enhances TRAF3 self-association, K63-linked ubiquitination, and RLR-induced IFN-β production.