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Theranostics 2019; 9(5):1369-1384. doi:10.7150/thno.32451 This issue Cite

Research Paper

Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells

Chunxiao Liu1*, Yifan Zhou2*, Mengdi Li1, Ying Wang1, Liu Yang1, Shigao Yang1, Yarui Feng1, Yinyin Wang1, Yangmeng Wang1, Fangli Ren1, Jun Li3, Zhongjun Dong2, Y. Eugene Chin4, Xinyuan Fu5, Li Wu2✉, Zhijie Chang1✉

1. State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing (100084), China.
2. Institute for Immunology, School of Medicine, Tsinghua University, Beijing (100084), China.
3. Institute of Immunology, PLA, The Third Military Medical University, Chongqing, (400038), China.
4. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai (200025), China.
5. Department of Biochemistry, South University of Science and Technology of China, Shenzhen (518055), China.
*These authors contributed equally to this work.

✉ Corresponding authors: Zhijie Chang Tel: (86-10)62785076; Fax: (86-10)62773624; E-mail: zhijiecedu.cn and Li Wu Tel: (86-10)62794835; Fax: (86-10)62794835;E-mail: wuliedu.cn

Citation:
Liu C, Zhou Y, Li M, Wang Y, Yang L, Yang S, Feng Y, Wang Y, Wang Y, Ren F, Li J, Dong Z, Chin YE, Fu X, Wu L, Chang Z. Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells. Theranostics 2019; 9(5):1369-1384. doi:10.7150/thno.32451. https://www.thno.org/v09p1369.htm
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Abstract

Graphic abstract

Nuclear factor-kappa B (NF-κB) activation is critical for innate immune responses. However, cellular-intrinsic regulation of NF-κB activity during inflammatory diseases remains incompletely understood. Ubiquitin-like protein 4A (UBL4A, GdX) is a small adaptor protein involved in protein folding, biogenesis and transcription. Yet, whether GdX has a role during innate immune response is largely unknown.

Methods: To investigate the involvement of GdX in innate immunity, we challenged GdX-deficient mice with lipopolysaccharides (LPS). To investigate the underlying mechanism, we performed RNA sequencing, real-time PCR, ELISA, luciferase reporter assay, immunoprecipitation and immunoblot analyses, flow cytometry, and structure analyses. To investigate whether GdX functions in inflammatory bowel disease, we generated dendritic cell (DC), macrophage (Mφ), epithelial-cell specific GdX-deficient mice and induced colitis with dextran sulfate sodium.

Results: GdX enhances DC and Mφ-mediated innate immune defenses by positively regulating NF-κB signaling. GdX-deficient mice were resistant to LPS-induced endotoxin shock and DSS-induced colitis. DC- or Mφ- specific GdX-deficient mice displayed alleviated mucosal inflammation. The production of pro-inflammatory cytokines by GdX-deficient DCs and Mφ was reduced. Mechanistically, we found that tyrosine-protein phosphatase non-receptor type 2 (PTPN2, TC45) and protein phosphatase 2A (PP2A) form a complex with RelA (p65) to mediate its dephosphorylation whereas GdX interrupts the TC45/PP2A/p65 complex formation and restrict p65 dephosphorylation by trapping TC45.

Conclusion: Our study provides a mechanism by which NF-κB signaling is positively regulated by an adaptor protein GdX in DC or Mφ to maintain the innate immune response. Targeting GdX could be a strategy to reduce over-activated immune response in inflammatory diseases.

Keywords: GdX/UBL4A, NF-κB, p65/RelA, inflammation, dendritic cells, macrophages

Citation styles

APA
Liu, C., Zhou, Y., Li, M., Wang, Y., Yang, L., Yang, S., Feng, Y., Wang, Y., Wang, Y., Ren, F., Li, J., Dong, Z., Chin, Y.E., Fu, X., Wu, L., Chang, Z. (2019). Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells. Theranostics, 9(5), 1369-1384. https://doi.org/10.7150/thno.32451.

ACS
Liu, C.; Zhou, Y.; Li, M.; Wang, Y.; Yang, L.; Yang, S.; Feng, Y.; Wang, Y.; Wang, Y.; Ren, F.; Li, J.; Dong, Z.; Chin, Y.E.; Fu, X.; Wu, L.; Chang, Z. Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells. Theranostics 2019, 9 (5), 1369-1384. DOI: 10.7150/thno.32451.

NLM
Liu C, Zhou Y, Li M, Wang Y, Yang L, Yang S, Feng Y, Wang Y, Wang Y, Ren F, Li J, Dong Z, Chin YE, Fu X, Wu L, Chang Z. Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells. Theranostics 2019; 9(5):1369-1384. doi:10.7150/thno.32451. https://www.thno.org/v09p1369.htm

CSE
Liu C, Zhou Y, Li M, Wang Y, Yang L, Yang S, Feng Y, Wang Y, Wang Y, Ren F, Li J, Dong Z, Chin YE, Fu X, Wu L, Chang Z. 2019. Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells. Theranostics. 9(5):1369-1384.

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