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Updated: Apr 24, 2026
Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Negative self-regulation of TLR9 signaling by its N-terminal proteolytic cleavage product
Sungwook Lee1, Dongju Kang1, Eun A Ra1
1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; and.
Abstract:
TLR signaling is essential to innate immunity against microbial invaders and must be tightly controlled. We have previously shown that TLR9 undergoes proteolytic cleavage processing by lysosomal proteases to generate two distinct fragments. The C-terminal cleavage product plays a critical role in activating TLR9 signaling; however, the precise role of the N-terminal fragment, which remains in lysosomes, in the TLR9 response is still unclear. In this article, we report that the N-terminal cleavage product negatively regulates TLR9 signaling. Notably, the N-terminal fragment promotes the aspartic protease-mediated degradation of the C-terminal fragment in endolysosomes. Furthermore, the N-terminal TLR9 fragment physically interacts with the C-terminal product, thereby inhibiting the formation of homodimers of the C-terminal fragment; this suggests that the monomeric C-terminal product is more susceptible to attack by aspartic proteases. Together, these results suggest that the N-terminal TLR9 proteolytic cleavage product is a negative self-regulator that prevents excessive TLR9 signaling activity.
Insights
The N-terminal fragment of Toll-like receptor 9 (TLR9) negatively regulates innate immunity signaling. This fragment promotes the degradation of the C-terminal fragment, preventing excessive TLR9 activation.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Toll-like receptor (TLR) signaling is crucial for innate immunity.
- TLR9 undergoes proteolytic cleavage into C-terminal and N-terminal fragments.
- The function of the N-terminal TLR9 fragment in immune regulation was previously unknown.
Purpose of the Study:
- To elucidate the role of the N-terminal TLR9 fragment in TLR9 signaling.
- To investigate the regulatory mechanisms of TLR9 activation.
Main Methods:
- Analysis of TLR9 proteolytic cleavage products.
- Assays to study protein-protein interactions.
- Investigation of protease-mediated degradation pathways.
Main Results:
- The N-terminal TLR9 fragment acts as a negative regulator of TLR9 signaling.
- This fragment enhances the degradation of the C-terminal fragment via aspartic proteases.
- The N-terminal fragment inhibits C-terminal fragment homodimerization, increasing susceptibility to degradation.
Conclusions:
- The N-terminal TLR9 fragment is a negative self-regulator of TLR9 signaling.
- This mechanism prevents overactivation of the innate immune response.
- Understanding this regulation offers insights into controlling TLR9-mediated immunity.
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