ArticleJournal of immunology (Baltimore, Md. : 1950)2016
Complex Negative Regulation of TLR9 by Multiple Proteolytic Cleavage Events.
Article in Journal of immunology (Baltimore, Md. : 1950), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- Article
- P-Glycoprotein Exacerbates Brain Injury Following Experimental Cerebral Ischemia by Promoting Proinflammatory Microglia Activation.Oxidative medicine and cellular longevity · 2023Article
- Molecular regulation of TLR signaling in health and disease: mechano-regulation of macrophages and TLR signaling.Innate immunity · 2020Review
- Participation of Endosomes in Toll-Like Receptor 3 Transportation Pathway in Murine Astrocytes.Frontiers in cellular neuroscience · 2020Article
- B Lymphocytes as Targets of the Immunomodulatory Properties of Human Amniotic Mesenchymal Stromal Cells.Frontiers in immunology · 2020Article
- Below the surface: The inner lives of TLR4 and TLR9.Journal of leukocyte biology · 2019Review
- Immunomodulatory nanogels overcome restricted immunity in a murine model of gut microbiome-mediated metabolic syndrome.Science advances · 2019Article
- TLR-7 Stress Signaling in Differentiating and Mature Eosinophils Is Mediated by the Prolyl Isomerase Pin1.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Toll-like receptor signaling in macrophages is regulated by extracellular substrate stiffness and Rho-associated coiled-coil kinase (ROCK1/2).International immunology · 2018Article
- Toll-like receptor expression and function differ between splenic marginal zone B cell lymphoma and splenic diffuse red pulp B cell lymphoma.Oncotarget · 2018Article
- TLR9 signaling activation at different stages in colorectal cancer and NF-kappaB expression.OncoTargets and therapy · 2018Article
- Tyrosine 870 of TLR9 is critical for receptor maturation rather than phosphorylation-dependent ligand-induced signaling.PloS one · 2018Article
- Nucleic acid-sensing TLRs: trafficking and regulation.Current opinion in immunology · 2017Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
TLR9 is an innate immune receptor important for recognizing DNA of host and foreign origin. A mechanism proposed to prevent excessive response to host DNA is the requirement for proteolytic cleavage of TLR9 in endosomes to generate a mature form of the receptor (TLR9(471-1032)). We previously described another cleavage event in the juxtamembrane region of the ectodomain that generated a dominant-negative form of TLR9. Thus, there are at least two independent cleavage events that regulate TLR9. In this study, we investigated whether an N-terminal fragment of TLR9 could be responsible for regulation of the mature or negative-regulatory form. We show that TLR9(471-1032), corresponding to the proteolytically cleaved form, does not function on its own. Furthermore, activity is not rescued by coexpression of the N-terminal fragment (TLR9(1-440)), inclusion of the hinge region (TLR9(441-1032)), or overexpression of UNC93B1, the last of which is critical for trafficking and cleavage of TLR9. TLR9(1-440) coimmunoprecipitates with full-length TLR9 and TLR9(471-1032) but does not rescue the native glycosylation pattern; thus, inappropriate trafficking likely explains why TLR9(471-1032) is nonfunctional. Lastly, we show that TLR9(471-1032) is also a dominant-negative regulator of TLR9 signaling. Together, these data provide a new perspective on the complexity of TLR9 regulation by proteolytic cleavage and offer potential ways to inhibit activity through this receptor, which may dampen autoimmune inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.