Super resolution microscopy reveals that caveolin-1 is required for spatial organization of CRFB1 and subsequent antiviral signaling in zebrafish.
Super resolution microscopy reveals that caveolin-1 is required for spatial organization of CRFB1 and subsequent antiviral signaling in zebrafish.
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DOI：
10.1371/journal.pone.0068759
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kim CH
中科院分区：
文献类型：
--
作者：
Gabor KA;Stevens CR;Pietraszewski MJ;Gould TJ;Shim J;Yoder JA;Lam SH;Gong Z;Hess ST;Kim CH
了解未受干扰膜内受体的空间分布和动态对于阐明它们在抗病毒信号传导中的作用至关重要，但传统的耐洗涤剂膜组分研究无法提供这一信息。小泡是许多信号通路的组成部分，这些膜结构域先前与病毒进入有关，但与抗病毒防御无关。本研究首次揭示了信号受体时空调控的重要性，以及聚类调控对下游信号传导的重要性。病毒逃避宿主细胞防御的一种新机制是通过破坏富小洞蛋白域内组织的信号分子簇来证明的。病毒感染导致斑马鱼I型干扰素受体（-R）亚基CRFB1簇的下调。超分辨率显微镜首次实现了CRFB1与含cav-1b膜结构域关联的单分子成像。引人注目的是，Cav-1b（小窝的主要蛋白质成分）的下调导致CRFB1簇分散。在体外和体内，CRFB1簇的分散通过消除下游信号传导导致抗病毒免疫反应受到抑制。这一反应强烈表明，CRFB1组织在含有cav-1b的膜域中对IFN介导的抗病毒防御至关重要，并提出了一种先前描述的抗病毒逃避策略，以改变IFN信号传导和抗病毒免疫反应。
Understanding spatial distribution and dynamics of receptors within unperturbed membranes is essential for elucidating their role in antiviral signaling, but conventional studies of detergent-resistant membrane fractions cannot provide this information. Caveolae are integral to numerous signaling pathways and these membrane domains have been previously implicated in viral entry but not antiviral defense. This study shows, for the first time, the importance of spatio-temporal regulation of signaling receptors and the importance of the regulation of clustering for downstream signaling. A novel mechanism for virus evasion of host cell defenses is demonstrated through disruption of clusters of signaling molecules organized within caveolin-rich domains. Viral infection leads to a downregulation in Caveolin-1b (Cav-1b), disrupting clusters of CRFB1, a zebrafish type I interferon receptor (–R) subunit. Super-resolution microscopy has enabled the first single-molecule imaging of CRFB1 association with cav-1b-containing membrane domains. Strikingly, downregulation of Cav-1b, the major protein component of caveolae, caused CRFB1 clusters to disperse. Dispersal of CRFB1 clusters led to a suppressed antiviral immune response both in vitro and in vivo, through abrogation of downstream signaling. This response strongly suggests that CRFB1 organization within cav-1b-containing membrane domains is critical for IFN-mediated antiviral defense and presents a previously undescribed antiviral evasion strategy to alter IFN signaling and the antiviral immune response.
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