Vangl2 Suppresses NF-κB Signaling and Ameliorates Sepsis by Promoting the Autophagic Degradation of p65

Conceitos essenciais

Vangl2 functions as a negative regulator of NF-κB signaling by promoting the autophagic degradation of the NF-κB subunit p65 through a Vangl2-PDLIM2-NDP52 axis.

Resumo

The study investigates the role of Vangl2, a core planar cell polarity (PCP) component, in regulating inflammatory responses and NF-κB signaling. The key findings are:

Vangl2 expression is upregulated in sepsis patients and in immune organs upon LPS stimulation. Myeloid-specific deletion of Vangl2 in mice leads to enhanced susceptibility to LPS-induced septic shock and increased production of pro-inflammatory cytokines.

Vangl2 negatively regulates LPS-induced NF-κB activation and proinflammatory cytokine production by interacting with and promoting the degradation of the NF-κB subunit p65.

Mechanistically, Vangl2 recruits the E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination of p65, which serves as a recognition signal for the cargo receptor NDP52 to mediate the selective autophagic degradation of p65.

The Vangl2-PDLIM2-NDP52 axis represents a negative feedback loop that suppresses excessive NF-κB-mediated inflammation and ameliorates sepsis.

Overall, the study uncovers a previously unrecognized role of Vangl2 in negatively regulating NF-κB signaling and inflammatory responses, providing insights into the crosstalk between autophagy and inflammatory diseases.

Estatísticas

Vangl2 mRNA levels are increased in peripheral blood mononuclear cells (PBMCs) from sepsis patients compared to healthy controls.
Myeloid-specific deletion of Vangl2 in mice leads to 100% mortality within 20 hours after high-dose LPS treatment, compared to 20% mortality in wild-type mice.
Vangl2-deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, as well as increased secretion of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) upon LPS stimulation.

Citações

"Vangl2 functions as a 'molecular brake' in the negative regulation of NF-κB signaling to prevent excessive and potentially harmful immune responses during sepsis."
"Vangl2 promotes the K63-linked ubiquitination of p65 and subsequent autophagic degradation through the cargo receptor NDP52, thereby suppressing NF-κB-mediated inflammation."
"The Vangl2-PDLIM2-NDP52 axis represents a negative feedback loop that ameliorates sepsis by limiting excessive NF-κB activation and proinflammatory cytokine production."

Principais Insights Extraídos De

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

by Lu,J., Zhang... às www.biorxiv.org 04-01-2023

https://www.biorxiv.org/content/10.1101/2023.03.30.534894v3

Perguntas Mais Profundas

How might the Vangl2-mediated regulation of NF-κB signaling be exploited for therapeutic interventions in other inflammatory diseases beyond sepsis?

The Vangl2-mediated regulation of NF-κB signaling presents a promising avenue for therapeutic interventions in various inflammatory diseases beyond sepsis. By understanding how Vangl2 suppresses NF-κB activation and promotes the autophagic degradation of p65, researchers can explore the development of targeted therapies for conditions where dysregulated NF-κB signaling plays a significant role in pathogenesis. For example, in inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other autoimmune disorders characterized by excessive inflammation, modulating the Vangl2-p65 interaction could help mitigate the inflammatory response. By targeting the Vangl2-NDP52 axis, it may be possible to enhance the selective autophagic degradation of pro-inflammatory proteins, thereby reducing inflammation and tissue damage in these conditions. Additionally, the identification of PDLIM2 as an E3 ubiquitin ligase involved in Vangl2-mediated p65 ubiquitination opens up opportunities for developing small molecule inhibitors or activators that can modulate this pathway for therapeutic benefit in a range of inflammatory diseases.

How might the potential crosstalk mechanisms between the Vangl2-dependent regulation of NF-κB and other developmental signaling pathways, such as Wnt/PCP, that are known to involve Vangl2?

The potential crosstalk mechanisms between Vangl2-dependent regulation of NF-κB and other developmental signaling pathways, such as Wnt/PCP, could have significant implications for both immune responses and tissue development. Vangl2 is a core component of the PCP pathway, which plays a crucial role in tissue morphogenesis and organ development. The interaction between Vangl2 and p65 in the context of NF-κB signaling regulation suggests a potential link between immune responses and developmental processes. It is possible that the same molecular machinery involved in Vangl2-mediated NF-κB regulation could also impact Wnt/PCP signaling, leading to coordinated responses in both immune cells and developing tissues. Understanding the crosstalk between these pathways could provide insights into how immune responses are integrated with tissue development and homeostasis, offering new opportunities for therapeutic interventions that target both inflammatory diseases and developmental disorders.

Could the Vangl2-NDP52 interaction and its role in selective autophagy be extended to the regulation of other immune-related proteins beyond p65, and how might this contribute to the maintenance of immune homeostasis?

The Vangl2-NDP52 interaction and its role in selective autophagy could indeed be extended to the regulation of other immune-related proteins beyond p65, thereby contributing to the maintenance of immune homeostasis. NDP52 is a cargo receptor involved in selective autophagy, targeting specific substrates for degradation in the autolysosome. By forming a complex with Vangl2, NDP52 may facilitate the selective autophagic degradation of a broader range of immune-related proteins beyond p65. This could include other transcription factors, signaling molecules, or regulatory proteins involved in immune responses. By promoting the degradation of these proteins through autophagy, the Vangl2-NDP52 axis could help regulate the intensity and duration of immune signaling, preventing excessive inflammation and maintaining immune homeostasis. Targeting this pathway could offer a novel approach to modulating immune responses and treating a variety of immune-related disorders where dysregulated protein turnover contributes to disease pathogenesis.