A surreal illustration of NF-κB p65 dimers interacting with DNA during inflammation.

Unlocking Immunity: How NF-κB p65's Dimerization Powers Inflammation

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Elliot Brynn in Science & Nature December 2025 • 5 min read.

"Discover the crucial role of NF-κB p65 dimerization and DNA-binding in driving inflammatory gene expression and immune responses."


In the complex world of immunology, transcription factors play pivotal roles in orchestrating gene expression and regulating immune responses. Among these, NF-κB p65 (RELA) stands out as a central regulator of innate immunity, influencing everything from inflammation to cell survival. While we've long known that transcription factors like NF-κB bind to DNA to do their job, increasing evidence suggests that their function may extend beyond simple DNA interaction.

Recent research has begun to uncover instances where transcription factors perform essential biological functions independent of their ability to bind directly to DNA. This raises a crucial question: How much do NF-κB p65's DNA-binding and dimerization capabilities truly contribute to its role in immune and inflammatory processes? Dimerization, the process of two identical molecules binding together, is essential for many proteins to function correctly.

To address this question, a new study meticulously investigated the relative importance of p65 DNA-binding and dimerization in human and murine cells. By using single amino acid mutants that prevent either DNA-binding or dimerization, the researchers teased apart the individual contributions of these functions, revealing surprising insights into the mechanics of inflammatory gene expression. This breakthrough enhances our understanding of NF-κB's regulatory mechanisms and suggests potential new avenues for therapeutic intervention in immune-related disorders.

The Dynamic Duo: Dimerization and DNA-Binding's Impact on Inflammation

A surreal illustration of NF-κB p65 dimers interacting with DNA during inflammation.

The study revealed that DNA-binding is essential for RelB-dependent stabilization of the NF-kB p100 protein, which, in turn, influences the processing of p100 into p52. Moreover, the antiapoptotic function of p65 and the expression of most TNF-α-induced genes heavily rely on p65's capacity to bind DNA and dimerize. Chromatin immunoprecipitation experiments confirmed that impaired DNA-binding and dimerization significantly reduce the association of p65 with chromatin, the complex of DNA and proteins that make up chromosomes.

However, the research also uncovered a nuanced picture. There exist p65-independent TNF-α-inducible genes, and a subset of p65 binding sites still allowed some residual chromatin association of the mutants. These sites were found to be enriched in activator protein 1 (AP-1) binding motifs, indicating potential cooperative mechanisms at play. It appears that chromatin priming and cooperation with other transcription factors like AP-1 can facilitate p65 chromatin association to some extent.

Key findings from the research:
  • DNA-binding is Essential: Required for RelB-dependent stabilization of NF-kB p100 protein.
  • Gene Expression: Most TNF-α-induced genes depend on p65's DNA-binding and dimerization abilities.
  • Chromatin Association: Impaired DNA-binding/dimerization diminishes p65's chromatin association.
  • Assisted Binding: AP-1 binding motifs suggest a mechanism of assisted p65 chromatin association.
Interestingly, when binding sites for both NF-κB and AP-1 were mutated in the IL-8 promoter, TNF-α-induced gene expression was greatly reduced. This highlights the interplay between these transcription factors in regulating inflammatory responses. These experiments also unveiled two new regulatory circuits controlling subunit abundance within the NF-kB system: p65 DNA-binding and dimerization are important for the expression of the NF-kB subunit RelB, which stabilizes the p52 precursor protein p100. Additionally, the study observed a rapid decay of the free dimerization-deficient NF-kB p65 subunit, ensuring a balanced subunit stoichiometry of NF-kB complexes.

Implications and Future Directions

This research provides critical insights into the complex mechanisms governing inflammatory gene expression. By demonstrating the importance of NF-κB p65 dimerization and DNA-binding, the study opens new avenues for targeted therapeutic interventions.

Understanding the interplay between NF-κB and other transcription factors, such as AP-1, could pave the way for novel strategies to modulate immune responses and treat inflammatory diseases. Furthermore, the discovery of regulatory circuits controlling subunit abundance within the NF-kB system offers additional targets for therapeutic manipulation.

Future research should focus on further elucidating the mechanisms underlying assisted p65 chromatin association and exploring the potential of targeting these mechanisms to treat inflammatory disorders. By unraveling the complexities of NF-κB signaling, we can develop more effective and precise therapies to combat a wide range of immune-related conditions.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

Everything You Need To Know

1

What is the primary function of NF-κB p65 (RELA) in the immune system, particularly concerning inflammation?

NF-κB p65, also known as RELA, is a transcription factor that plays a crucial role in regulating innate immunity. It influences various processes, including inflammation and cell survival. Recent research emphasizes the importance of NF-κB p65's DNA-binding and dimerization capabilities in facilitating inflammatory gene expression, which in turn impacts immune responses.

2

Why is the dimerization process important for NF-κB p65, especially in the context of TNF-α-induced genes and immune responses?

Dimerization is essential for the proper functioning of many proteins, including NF-κB p65. In the context of immune responses, the study shows that the antiapoptotic function of p65 and the expression of most TNF-α-induced genes heavily rely on p65's capacity to dimerize. Without proper dimerization, NF-κB p65 cannot effectively carry out its functions in regulating inflammation and immune responses.

3

How does the DNA-binding capability of NF-κB p65 contribute to its role in stabilizing NF-kB p100 protein and influencing gene expression?

The research indicates that DNA-binding is required for RelB-dependent stabilization of the NF-kB p100 protein. Furthermore, the expression of most TNF-α-induced genes depends on p65's DNA-binding abilities. Impaired DNA-binding significantly reduces the association of p65 with chromatin. This interaction is a necessary initial step for the effective expression of genes involved in inflammatory responses.

4

What role does the interplay between NF-κB p65 and Activator Protein 1 (AP-1) play in regulating inflammatory responses, particularly within the IL-8 promoter?

The interplay between NF-κB p65 and AP-1 in the IL-8 promoter demonstrates a cooperative mechanism in regulating inflammatory responses. When binding sites for both NF-κB and AP-1 are mutated in the IL-8 promoter, TNF-α-induced gene expression is greatly reduced. This highlights the importance of multiple transcription factors working together to fine-tune gene expression during inflammation. This suggests that AP-1 can assist p65 chromatin association to some extent.

5

What new regulatory circuits were discovered regarding NF-κB p65's DNA-binding and dimerization, and how do these findings impact our understanding of inflammatory gene expression?

The study unveiled new regulatory circuits showing that p65 DNA-binding and dimerization are important for the expression of the NF-kB subunit RelB, which stabilizes the p52 precursor protein p100. Additionally, a rapid decay of the free dimerization-deficient NF-kB p65 subunit was observed, ensuring a balanced subunit stoichiometry of NF-kB complexes. These discoveries further enhance our understanding of the NF-kB system's complexity and how it maintains a balanced inflammatory response.

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