title: Negative self-regulation of TLR9 signaling by its N-terminal proteolytic cleavage product.
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.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; and.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; and.
authors.forename: Dongju
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; and.
authors.forename: Eun A
authors.initials: EA
authors.lastname: Ra
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; and.
authors.forename: Taeyun A
authors.initials: TA
authors.lastname: Lee
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02115.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; and bypark@yonsei.ac.kr.
authors.forename: Boyoun
authors.initials: B
authors.lastname: Park
mesh_terms: D000818:Animals; D057055:Aspartic Acid Proteases / Q000235:genetics / Q000276:immunology; D011992:Endosomes / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D055503:Protein Multimerization / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*
chemical_list: C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D057055:Aspartic Acid Proteases