The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry.
The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry.
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DOI：
10.1016/j.chom.2013.03.006
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发表时间：
2013-04-17
影响因子：
30.3
通讯作者：
Jung JU
中科院分区：
文献类型：
--
作者：
Amini-Bavil-Olyaee S;Choi YJ;Lee JH;Shi M;Huang IC;Farzan M;Jung JU
囊泡膜蛋白相关蛋白A（VAPA）和氧固醇结合蛋白（OSBP）调节细胞内胆固醇稳态，这是许多病毒感染所必需的。在进入过程中，病毒或含病毒的囊泡可以与内体膜融合以介导病毒粒子的胞质释放，并且内体胆固醇的改变可以抑制该侵入步骤。我们发现，抗病毒效应蛋白干扰素诱导的跨膜蛋白3（IFITM3）与VAPA相互作用，并防止其与OSBP的关联，从而破坏细胞内胆固醇稳态，抑制病毒进入。通过改变VAPA-OSBP功能，IFITM3诱导胆固醇在多泡体和晚期内体中的显著积累，这抑制了腔内含有病毒体的囊泡与内体膜的融合，从而阻断病毒释放到胞质溶胶中。因此，VAPA基因的异位表达或缺失深刻地影响IFITM3介导的病毒进入抑制。因此，IFITM3破坏细胞内胆固醇稳态以阻断病毒进入，进一步强调了胆固醇在病毒感染中的重要性。► IFITM3拮抗VAPA-OSBP功能，扰乱细胞内胆固醇稳态► IFITM3诱导的内体胆固醇增加抑制囊泡融合和病毒进入► VAPA释放IFITM3诱导的囊泡融合抑制，允许病毒进入
Vesicle-membrane-protein-associated protein A (VAPA) and oxysterol-binding protein (OSBP) regulate intracellular cholesterol homeostasis, which is required for many virus infections. During entry, viruses or virus-containing vesicles can fuse with endosomal membranes to mediate the cytosolic release of virions, and alterations in endosomal cholesterol can inhibit this invasion step. We show that the antiviral effector protein interferon-inducible transmembrane protein 3 (IFITM3) interacts with VAPA and prevents its association with OSBP, thereby disrupting intracellular cholesterol homeostasis and inhibiting viral entry. By altering VAPA-OSBP function, IFITM3 induces a marked accumulation of cholesterol in multivesicular bodies and late endosomes, which inhibits the fusion of intraluminal virion-containing vesicles with endosomal membranes and thereby blocks virus release into the cytosol. Consequently, ectopic expression or depletion of the VAPA gene profoundly affects IFITM3-mediated inhibition of viral entry. Thus, IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry, further underscoring the importance of cholesterol in virus infection. ► IFITM3 antagonizes VAPA-OSBP function to disturb intracellular cholesterol homeostasis ► IFITM3-induced endosomal cholesterol increase inhibits vesicle fusion and viral entry ► VAPA releases IFITM3-induced inhibition of vesicle fusion, allowing viral entry
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