Inhibition of IRF5 cellular activity with cell-penetrating peptides that target homodimerization
Inhibition of IRF5 cellular activity with cell-penetrating peptides that target homodimerization
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DOI：
10.1126/sciadv.aay1057
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发表时间：
2020-05-01
期刊：
影响因子：
13.6
通讯作者：
Barnes, Betsy J.
中科院分区：
文献类型：
--
作者：
Banga, Jaspreet;Srinivasan, Dinesh;Barnes, Betsy J.
转录因子干扰素调节因子 5 (IRF5) 在 Toll、核苷酸结合寡聚结构域和视黄酸诱导基因 I 样受体下游的病原体诱导免疫中发挥重要作用，并且是一种自身免疫易感基因。通常，IRF5 在细胞质中不活跃，受到刺激后，IRF5 会经历翻译后修饰、同二聚化和核转位，其中二聚体介导促炎基因转录。在这里，我们报告了破坏 IRF5 同二聚化的细胞穿透肽 (CPP) 的合理设计。生化和成像分析表明，IRF5-CPP 具有细胞渗透性、无细胞毒性，并直接与内源性 IRF5 结合。 IRF5-CPP 具有选择性并提供细胞类型和物种特异性抑制。在浆细胞样树突状细胞中，IRF5介导的干扰素-α产生的抑制对应于核磷酸化IRF5 [p(Ser(462))IRF5]的剂量依赖性减少，但对pIRF5水平没有影响。这些数据支持 IRF5-CPP 在磷酸化下游发挥作用。总之，数据支持 IRF5-CPP 作为探测疾病中 IRF5 激活和功能的新工具的实用性。
The transcription factor interferon regulatory factor 5 (IRF5) plays essential roles in pathogen-induced immunity downstream of Toll-, nucleotide-binding oligomerization domain-, and retinoic acid-inducible gene I-like receptors and is an autoimmune susceptibility gene. Normally, inactive in the cytoplasm, upon stimulation, IRF5 undergoes posttranslational modification(s), homodimerization, and nuclear translocation, where dimers mediate proinflammatory gene transcription. Here, we report the rational design of cell-penetrating peptides (CPPs) that disrupt IRF5 homodimerization. Biochemical and imaging analysis shows that IRF5-CPPs are cell permeable, noncytotoxic, and directly bind to endogenous IRF5. IRF5-CPPs were selective and afforded cell type- and species-specific inhibition. In plasmacytoid dendritic cells, inhibition of IRF5-mediated interferon-alpha production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser(462))IRF5], with no effect on pIRF5 levels. These data support that IRF5-CPPs function downstream of phosphorylation. Together, data support the utility of IRF5-CPPs as novel tools to probe IRF5 activation and function in disease.