Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation

Van Gogh-like 2 (Vangl2), a core planar cell polarity component, plays an important role in polarized cellular and tissue morphology induction, growth development, and cancer. However, its role in regulating inflammatory responses remains elusive. Here, we report that Vangl2 is upregulated in patients with sepsis and identify Vangl2 as a negative regulator of The nuclear factor-kappaB (NF-κB) signaling by regulating the protein stability and activation of the core transcription component p65. Mice with myeloid-specific deletion of Vangl2 ( Vangl2 ΔM ) are hypersusceptible to lipopolysaccharide (LPS)-induced septic shock. Vangl2-deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, therefore, promoting the secretion of proinflammatory cytokines after LPS stimulation. Mechanistically, NF-κB signaling-induced-Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on p65, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, these findings demonstrate Vangl2 as a suppressor of NF-κB-mediated inflammation and provide insights into the crosstalk between autophagy and inflammatory diseases.

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Publication Details

Journal
eLife
Published
2024-09-13
DOI
https://doi.org/10.7554/elife.87935.4
Citations
3
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
1.16

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article

Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation

Jianwu Yang, Xiao Yu, Qingyue Xiao, Lian He et al.
3 citations
eLife
Autophagy in Disease and Therapy
1.16
article

Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation

Jianwu Yang, Xiao Yu, Qingyue Xiao, Lian He, Peng Tan, Yingchao Xie, Jiansen Lu, Zijing Song, Ke Zeng, Yufen Zhang, Z. Hu, Huaji Jiang, Chenglong Pan, Hongyu Li, Xiaochun Bai, Jiahuan Zhang, Dan Wu
article en
3 citations

Abstract

Van Gogh-like 2 (Vangl2), a core planar cell polarity component, plays an important role in polarized cellular and tissue morphology induction, growth development, and cancer. However, its role in regulating inflammatory responses remains elusive. Here, we report that Vangl2 is upregulated in patients with sepsis and identify Vangl2 as a negative regulator of The nuclear factor-kappaB (NF-κB) signaling by regulating the protein stability and activation of the core transcription component p65. Mice with myeloid-specific deletion of Vangl2 ( Vangl2 ΔM ) are hypersusceptible to lipopolysaccharide (LPS)-induced septic shock. Vangl2-deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, therefore, promoting the secretion of proinflammatory cytokines after LPS stimulation. Mechanistically, NF-κB signaling-induced-Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on p65, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, these findings demonstrate Vangl2 as a suppressor of NF-κB-mediated inflammation and provide insights into the crosstalk between autophagy and inflammatory diseases.

eLifeVol. 12
Broad Institute (US), Southern University of Science and Technology (CN), Shantou University (CN), Yue Bei People's Hospital (CN), Cell Technology (China) (HK), Guangdong Academy of Medical Sciences (CN), Guangdong Provincial People's Hospital (CN), Southern Medical University (CN), Texas A&M University (US)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, Basic and Applied Basic Research Foundation of Guangdong Province
Good health and well-being
Openalex Percentile: Top 20%
Autophagy in Disease and Therapy
1.16
DOIOpen Access PDFOpenAlex
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