Pattern recognition receptor mediated innate immune response requires a Rif-dependent pathway
Pattern recognition receptor mediated innate immune response requires a Rif-dependent pathway
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DOI：
10.1016/j.jaut.2022.102975
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发表时间：
2022-12-15
影响因子：
12.8
通讯作者：
Fan，Lifei
中科院分区：
文献类型：
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作者：
Tian，Xiaoxia;Nanding，Kathleen;Fan，Lifei
小GTP酶通过动态调节肌动蛋白细胞骨架在细胞形态、运动和粘附中起关键作用。小的Rho GTRif/RhoF（Rho in filopodia）调节细胞中丝状伪足和应力纤维的形成。Rif在免疫系统中的许多细胞类型中高度表达;然而，它在免疫系统功能中的作用尚不清楚。在本研究中，我们发现Rif基因的表达是NF-κB活化所必需的，并且从Rif基因敲除（Rif KO）小鼠骨髓来源的树突状细胞（BMDCs）诱导的成熟树突状细胞（成熟DCs）在LPS刺激下显示I-κBα降解受损，TNF-α分泌减少和p38 MAPK磷酸化。有趣的是，我们发现TLR激动剂，如LPS和poly（I：C），以及细菌毒力因子SopE可以诱导单核细胞THP-1细胞中Rif激活的瞬时增加。此外，Rif被发现是TLR 4、TLR 3和节点体信号传导复合物的组成部分。我们进一步确定Src酪氨酸激酶作为Rif在细菌和病毒诱导的免疫应答中的上游激活剂。此外，活化的Rif诱导转录因子如NF-κB、AP-1和IRF-3的活化，并通过分泌IL-6、IL-8或TNFα介导炎症。PRR激活Rif以多种方式有助于保护宿主抵抗入侵微生物的反应。总之，这项研究表明，Rif是不可缺少的细胞外和细胞内的模式识别受体介导的先天免疫反应。Rif具有广泛的抗病原体作用，了解这种小Rho GTdR干扰先天免疫系统的分子机制将有助于开发抗感染剂的治疗方法。
Small GTPases play critical roles in cell morphology, movement, and adhesion by dynamic regulation of actin cytoskeleton. The small Rho GTPase Rif/RhoF (Rho in filopodia) regulates the formation of filopodia and stress fibers in cells. Rif is highly expressed in a number of cell types in the immune system; however, it's role in immune system function is unclear. In this research, we found that Rif expression is necessary for NF-κB activation in primary immune cells, and mature dendritic cell (mature DCs) induced from Bone Marrow-Derived Dendritic Cells (BMDCs) isolated from Rif knock out (Rif KO) mice displayed impaired degradation of I-κBα, as well as reduced TNF-α secretion and p38 MAPK phosphorylation under LPS stimulation. Interestingly, we revealed that TLR agonists, such as LPS and poly (I:C), as well as bacterial virulence factor SopE could induce a transient increase in Rif activation in monocytes THP-1 cells. Furthermore, Rif was found to be an integral part of the TLR4, TLR3 and nodosome signaling complex. We further identified Src tyrosine kinases as upstream activator of Rif in both bacterial and viral induced immune responses. Moreover, activated Rif induces activation of transcription factors, such as NF-κB, AP-1 and IRF-3, and mediates inflammation through secretion of IL-6, IL-8 or TNFα. Rif activation by PRRs contributes in a variety of ways to protective host responses against invading microbes. Taken together, this study reveals that Rif is indispensable for both extracellular and intracellular pattern-recognition receptor-mediated innate immune responses. Rif possess broad anti-pathogenic effect and understanding of the molecular mechanisms by which this small Rho GTPase interferes with innate immune system will be beneficial to develop therapies against infectious agents.