Human beta defensin-3 mediated activation of β-catenin during human respiratory syncytial virus infection: interaction of HBD3 with LDL receptor-related protein 5.
Human beta defensin-3 mediated activation of β-catenin during human respiratory syncytial virus infection: interaction of HBD3 with LDL receptor-related protein 5.
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DOI：
10.3389/fmicb.2023.1186510
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发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
呼吸道合胞病毒（RSV）是一种非分节负义RNA病毒，属于副粘病毒科。RSV感染呼吸道，引起婴儿、老年人和免疫功能低下患者的肺炎和细支气管炎。目前仍然缺乏对抗呼吸道合胞病毒感染的有效临床治疗方案和疫苗。因此，为了制定有效的治疗干预措施，了解RSV感染过程中病毒与宿主的相互作用是必要的。β-catenin蛋白的细胞质稳定导致典型的无翼(Wnt)/β-catenin信号通路的激活，最终导致t细胞因子/淋巴细胞增强因子（TCF/LEF）转录因子调控的各种基因的转录激活。该通路参与多种生物生理功能。我们的研究表明RSV感染人肺上皮A549细胞可触发β-catenin蛋白稳定并诱导β-catenin介导的转录活性。功能上，激活的β-catenin通路在RSV感染肺上皮细胞时促进了促炎反应。对β-catenin抑制剂和缺乏最佳β-catenin活性的A549细胞的研究表明，rsv感染细胞的促炎趋化因子白介素-8 （IL-8）释放显著减少。在机制上，我们的研究揭示了细胞外人β防御素-3 （HBD3）在RSV感染期间与细胞表面Wnt受体LDL受体相关蛋白-5 （LRP5）相互作用，激活非典型Wnt独立的β-catenin途径的作用。我们发现RSV感染细胞中HBD3的基因表达和释放，沉默HBD3的表达导致RSV感染期间β-catenin蛋白的稳定性降低。此外，我们观察到细胞外HBD3与细胞表面定位的LRP5蛋白结合，我们的硅和蛋白相互作用研究强调了HBD3与LRP5的直接相互作用。因此，我们的研究确定了β-catenin通路是RSV感染人肺上皮细胞过程中促炎反应的关键调节因子。在RSV感染期间，这一途径是通过非典型的Wnt独立机制诱导的，该机制涉及细胞外HBD3的旁分泌/自分泌作用，通过直接与LRP5受体相互作用激活细胞表面Wnt受体复合物。
Respiratory Syncytial Virus (RSV) is a non-segmented negative-sense RNA virus belonging to the paramyxovirus family. RSV infects the respiratory tract to cause pneumonia and bronchiolitis in infants, elderly, and immunocompromised patients. Effective clinical therapeutic options and vaccines to combat RSV infection are still lacking. Therefore, to develop effective therapeutic interventions, it is imperative to understand virus-host interactions during RSV infection. Cytoplasmic stabilization of β-catenin protein results in activation of canonical Wingless (Wnt)/β-catenin signaling pathway that culminates in transcriptional activation of various genes regulated by T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors. This pathway is involved in various biological and physiological functions. Our study shows RSV infection of human lung epithelial A549 cells triggering β-catenin protein stabilization and induction of β-catenin mediated transcriptional activity. Functionally, the activated β-catenin pathway promoted a pro-inflammatory response during RSV infection of lung epithelial cells. Studies with β-catenin inhibitors and A549 cells lacking optimal β-catenin activity demonstrated a significant loss of pro-inflammatory chemokine interleukin-8 (IL-8) release from RSV-infected cells. Mechanistically, our studies revealed a role of extracellular human beta defensin-3 (HBD3) in interacting with cell surface Wnt receptor LDL receptor-related protein-5 (LRP5) to activate the non-canonical Wnt independent β-catenin pathway during RSV infection. We showed gene expression and release of HBD3 from RSV-infected cells and silencing of HBD3 expression resulted in reduced stabilization of β-catenin protein during RSV infection. Furthermore, we observed the binding of extracellular HBD3 with cell surface localized LRP5 protein, and our in silico and protein–protein interaction studies have highlighted a direct interaction of HBD3 with LRP5. Thus, our studies have identified the β-catenin pathway as a key regulator of pro-inflammatory response during RSV infection of human lung epithelial cells. This pathway was induced during RSV infection via a non-canonical Wnt-independent mechanism involving paracrine/autocrine action of extracellular HBD3 activating cell surface Wnt receptor complex by directly interacting with the LRP5 receptor.
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影响因子：
8
作者：
COLOVOS, C;YEATES, TO
通讯作者：
YEATES, TO
Wnt1 通过上调清道夫受体 A 和 NF-kB 参与脂多糖诱导的炎症。
影响因子：
5.1
作者：
Zhao, Wenting;Sun, Zewei;Wang, Shuai;Li, Zhenwei;Zheng, Liangrong
通讯作者：
Zheng, Liangrong
DOI：
10.1152/ajplung.1995.269.6.l865
发表时间：
1995-12-01
影响因子：
4.9
作者：
Fiedler, MA;WernkeDollries, K;Stark, JM
通讯作者：
Stark, JM
DOI：
10.1073/pnas.0505259102
发表时间：
2005-11-29
影响因子：
11.1
作者：
Clément-Lacroix, P;Ai, MR;Rawadi, G
通讯作者：
Rawadi, G
影响因子：
15.3
作者：
Bazzoni, F;Cassatella, M A;Rossi, F;Ceska, M;Dewald, B;Baggiolini, M
通讯作者：
Baggiolini, M