Sequence determinants in the cathelicidin LL-37 that promote inflammation via presentation of RNA to scavenger receptors
| العنوان: | Sequence determinants in the cathelicidin LL-37 that promote inflammation via presentation of RNA to scavenger receptors |
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| المؤلفون: | Richard L. Gallo, Tatsuya Dokoshi, Alan M. O’Neill, Elizabeth Wei Chia Luo, Nikhil Nitin Kulkarni, Gerard C. L. Wong |
| المصدر: | The Journal of Biological Chemistry The Journal of biological chemistry, vol 297, iss 1 |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Transcription, Genetic, medicine.medical_treatment, Inbred C57BL, Biochemistry, Medical and Health Sciences, Cathelicidin, Mice, Double-Stranded, antimicrobial peptides, SR, scavenger receptor, Receptors, cathelicidin, Innate, Receptor, GAS, group A Streptococcus, Receptors, Scavenger, Alanine, LDH, lactate dehydrogenase, Chemistry, LL-37, 37-amino acid peptide, UCSD, University of California, San Diego, SAXS, small-angle X-ray scattering, interferon, Alanine scanning, Biological Sciences, Cell biology, IL-6, interleukin 6, Infectious Diseases, LL-34, 34-amino acid peptide, Interferon Type I, qRT-PCR, quantitative RT-PCR, Female, NHEK, normal human epidermal keratinocyte, Transcription, RIGI, retinoic acid–inducible gene I, Research Article, Protein Binding, Signal Transduction, Biochemistry & Molecular Biology, skin, HDMEC, human dermal microvascular endothelial cell, MIC, minimum inhibitory concentration, Antimicrobial peptides, I20P, proline at isoleucine position 20, IRF7, interferon regulatory factor 7, Biophysical Phenomena, Scavenger, MAVS, mitochondrial antiviral signaling, Cell Line, 03 medical and health sciences, Structure-Activity Relationship, Genetic, Cathelicidins, GO, Gene Ontology, medicine, Genetics, Animals, Humans, Amino Acid Sequence, Molecular Biology, RNA, Double-Stranded, Inflammation, Innate immune system, 030102 biochemistry & molecular biology, Cell Membrane, Immunity, RNA, Cell Biology, cytokines, Immunity, Innate, Toll-Like Receptor 3, Mice, Inbred C57BL, 030104 developmental biology, Emerging Infectious Diseases, Gene Expression Regulation, Chemical Sciences, TBK1, TANK-binding kinase 1, Mutation, Nucleic acid, Antimicrobial Cationic Peptides |
| الوصف: | Cathelicidins such as the human 37-amino acid peptide (LL-37) are peptides that not only potently kill microbes but also trigger inflammation by enabling immune recognition of endogenous nucleic acids. Here, a detailed structure-function analysis of LL-37 was performed to understand the details of this process. Alanine scanning of 34-amino acid peptide (LL-34) showed that some variants displayed increased antimicrobial activity against Staphylococcus aureus and group A Streptococcus. In contrast, different substitutions clustered on the hydrophobic face of the LL-34 alpha helix inhibited the ability of those variants to promote type 1 interferon expression in response to U1 RNA or to present U1 to the scavenger receptor (SR) B1 on the keratinocyte cell surface. Small-angle X-ray scattering experiments of the LL-34 variants LL-34, F5A, I24A, and L31A demonstrated that these peptides form cognate supramolecular structures with U1 characterized by inter-dsRNA spacings of approximately 3.5nm, a range that has been previously shown to activate toll-like receptor 3 by the parent peptide LL-37. Therefore, while alanine substitutions on the hydrophobic face of LL-34 led to loss of binding to SRs and the complete loss of autoinflammatory responses in epithelial and endothelial cells, they did not inhibit the ability to organize with U1 RNA in solution to associate with toll-like receptor 3. These observations advance our understanding of how cathelicidin mediates the process of innate immune self-recognition to enable inert nucleic acids to trigger inflammation. We introduce the term "innate immune vetting" to describe the capacity of peptides such as LL-37 to enable certain nucleic acids to become an inflammatory stimulus through SR binding prior to cell internalization. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7653124affc7f3c4f58a75aed7ae4eb7Test http://europepmc.org/articles/PMC8214221Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7653124affc7f3c4f58a75aed7ae4eb7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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