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Absence of GdX/UBL4AProtects againstInflammatory Diseasesby Regulating NF-кBSignaling inMacrophages andDendritic Cells Chunxiao LiuYifan ZhouMengdi Li2019 год

Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells
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Аннотация: 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.
Год издания: 2019
Авторы: Chunxiao Liu, Yifan Zhou, Mengdi Li, Ying Wang, Yang Liu, Shigao Yang, Yarui Feng, Yinyin Wang, Yangmeng Wang, Fangli Ren, Jun Li, Zhongjun Dong, Y. Eugene Chin, Xin‐Yuan Fu, Wu Li, Zhijie Chang
Издательство: Ivyspring International Publisher
Источник: Theranostics
Ключевые слова: Immune Response and Inflammation, Immunotherapy and Immune Responses, NF-κB Signaling Pathways
Другие ссылки: Theranostics (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)