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

Author:

Lu Jiansen12ORCID,Zhang Jiahuan3,Jiang Huaji24,Hu Zhiqiang2,Zhang Yufen2,He Lian56,Yang Jianwu2,Xie Yingchao2,Wu Dan2,Li Hongyu2,Zeng Ke2,Tan Peng57,Xiao Qingyue8,Song Zijing8,Pan Chenglong1,Bai Xiaochun8ORCID,Yu Xiao29ORCID

Affiliation:

1. Department of Joint Surgery, the Fifth Affiliated Hospital, Southern Medical University

2. Department of Immunology, School of Basic Medical Sciences, Southern Medical University

3. Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou

4. Department of Orthopaedics, Yue Bei People’s Hospital Affiliated to Medical College of Shantou University

5. Department of Pharmacology, School of Medicine, Southern University of Science and Technology

6. Institute of Biosciences and Technology, College of Medicine, Texas A&M University

7. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge

8. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University

9. Guangdong Provincial Key Lab of Single Cell Technology and Application, Southern Medical University

Abstract

Van Gogh-like 2 (Vangl2), a core planar cell polarity (PCP) 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 NF-κB signaling by regulating the protein stability and activation of the core transcription component p65. Mice with myeloid-specific deletion of Vangl2 ( Vangl2 Δ M ) are hypersusceptible to lipopolysaccharide (LPS)-induced septic shock. Vangl2 deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, therefore, promoting the secretion of pro-inflammatory 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.

Publisher

eLife Sciences Publications, Ltd

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