树突状细胞中tlr9驱动的s -棕榈酰化揭示了免疫和代谢蛋白靶点

IF 3.7 3区 医学 Q2 IMMUNOLOGY
Juan N. Quiroz, Malte Sielaff, Daria Kondrateva, Fatima Boukhallouk, Gloria J. Godoy, Cecilia R. Molina, Brecht Moonen, Claudia C. Motran, Jeroen Bogie, Hugo D. Luján, Stefan Tenzer, Tim Sparwasser, Luciana Berod
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引用次数: 0

摘要

树突状细胞(DCs)依靠toll样受体9 (TLR9)检测微生物DNA中未甲基化的CpG基序,触发必要的免疫反应。虽然TLR9激活的下游信号通路已经被很好地表征,但它们对s -棕榈酰化的影响尚不清楚。s -棕榈酰化涉及棕榈酸与半胱氨酸残基的可逆附着,在调节蛋白质功能中起着至关重要的作用,并由棕榈酰酰基转移酶(PATs) ZDHHC家族催化。在这项研究中,我们研究了静息和CpGB激活TLR9后骨髓源性GM-CSF DCs (GM-DCs)的s -棕榈酰化蛋白质组。利用点击化学兼容的类似物17-十八环酸(17-ODYA)和基于质谱(MS)的蛋白质组学,我们表征了响应TLR9激活的s -棕榈酰化的动态重塑。这包括涉及免疫和代谢途径的靶标的富集。小鼠和人dc的转录组学分析显示tlr9驱动pat编码基因的调节。随后,我们探索了Zdhhc9表达在DCs中对s -棕榈酰化的调节作用。利用基因敲除方法,我们确定了潜在的与ZDHHC9活性相关的候选蛋白靶点。有趣的是,单独调节Zdhhc9的表达并不影响DC的成熟,这表明其他pat可能会补偿其活性。总之,我们的研究结果揭示了s -棕榈酰化介导的TLR9信号传导的新调控层。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

TLR9-Driven S-Palmitoylation in Dendritic Cells Reveals Immune and Metabolic Protein Targets

TLR9-Driven S-Palmitoylation in Dendritic Cells Reveals Immune and Metabolic Protein Targets

Dendritic cells (DCs) rely on Toll-like receptor 9 (TLR9) to detect unmethylated CpG motifs in microbial DNA, triggering essential immune responses. While the downstream signaling pathways of TLR9 activation are well characterized, their impact on S-palmitoylation is unknown. S-palmitoylation, involving the reversible attachment of palmitic acid to cysteine residues, plays a crucial role in regulating protein function and is catalyzed by the ZDHHC family of palmitoyl-acyltransferases (PATs). In this study, we investigated the S-palmitoylated proteome of bone marrow-derived GM-CSF DCs (GM-DCs) at resting and following TLR9 activation with CpGB. Using the click-chemistry-compatible analog 17-octadecynoic acid (17-ODYA) and mass spectrometry (MS)-based proteomics, we characterized dynamic remodeling of S-palmitoylation in response to TLR9 activation. This included enrichment of targets involved in immune and metabolic pathways. Transcriptomic analysis of mice and human DCs revealed TLR9-driven modulation of PAT-encoding genes. Subsequently, we explored the contribution of Zdhhc9 expression to the regulation of S-palmitoylation in DCs. Using gene knockout approaches, we identified candidate protein targets potentially linked to ZDHHC9 activity. Interestingly, modulation of Zdhhc9 expression alone did not influence DC maturation, suggesting that other PATs might compensate for its activity. Together, our findings reveal a novel layer of regulation in TLR9 signaling mediated by S-palmitoylation.

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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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