Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product
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 ac...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Association of Immunologists
2015
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| Online Access: | http://hdl.handle.net/1721.1/96698 https://orcid.org/0000-0002-1090-6071 |
| _version_ | 1826202863999647744 |
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| author | Ploegh, Hidde Lee, Sungwook Kang, Dongju Ra, Eun A. Lee, Taeyun A. Park, Boyoun |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ploegh, Hidde Lee, Sungwook Kang, Dongju Ra, Eun A. Lee, Taeyun A. Park, Boyoun |
| author_sort | Ploegh, Hidde |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:21:40Z |
| format | Article |
| id | mit-1721.1/96698 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:21:40Z |
| publishDate | 2015 |
| publisher | American Association of Immunologists |
| record_format | dspace |
| spelling | mit-1721.1/966982022-10-01T09:01:58Z Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product Ploegh, Hidde Lee, Sungwook Kang, Dongju Ra, Eun A. Lee, Taeyun A. Park, Boyoun Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Ploegh, Hidde 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. Korea (South). Ministry of Education, Science and Technology (MEST) (National Research Foundation of Korea. Grant 2011-0015372) Korea (South). Ministry of Education, Science and Technology (MEST) (National Research Foundation of Korea. Grant 2010-0009203) Korea. Ministry of Health and Welfare. National Research and Development Program for Cancer Control 2015-04-22T16:06:56Z 2015-04-22T16:06:56Z 2014-09 2014-01 Article http://purl.org/eprint/type/JournalArticle 0022-1767 1550-6606 http://hdl.handle.net/1721.1/96698 Lee, S., D. Kang, E. A. Ra, T. A. Lee, H. L. Ploegh, and B. Park. “Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product.” The Journal of Immunology 193, no. 7 (September 3, 2014): 3726–3735. https://orcid.org/0000-0002-1090-6071 en_US http://dx.doi.org/10.4049/jimmunol.1400210 Journal of Immunology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association of Immunologists PMC |
| spellingShingle | Ploegh, Hidde Lee, Sungwook Kang, Dongju Ra, Eun A. Lee, Taeyun A. Park, Boyoun Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product |
| title | Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product |
| title_full | Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product |
| title_fullStr | Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product |
| title_full_unstemmed | Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product |
| title_short | Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product |
| title_sort | negative self regulation of tlr9 signaling by its n terminal proteolytic cleavage product |
| url | http://hdl.handle.net/1721.1/96698 https://orcid.org/0000-0002-1090-6071 |
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