Cell Host & Microbe:IFITM3抗病毒机制

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原帖由ipsvirus 2013-4-22 15:05 发表于老论坛


近日，美国南加州大学的研究人员对IFITM3的抗病毒机制有了新进展，并将研究成果发表在Cell Host & Microbe杂志上。

当病毒感染机体后会激活表达干扰素，干扰病毒复制。同时干扰素也会诱导表达多种蛋白发挥抗病毒作用，IFN诱导蛋白IFITM3就是其中之一。IFITM3已报道过对于流感等病毒都具有有效的抗病毒作用，此研究对其具体机制进行了深入研究，发现其能在病毒入侵阶段发挥功能。

研究发现IFITM3能够破坏囊膜相关蛋白VAPA和OSBP的相互作用，从而影响胆固醇的转运，破坏胞内胆固醇稳态，使得胞内体中的胆固醇积累，病毒无法从胞内体中进入到细胞质中进行复制。

此项研究成果有望为抗病毒治疗提供新的靶点。

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The Antiviral Effector IFITM3 Disrupts Intracellular Cholesterol Homeostasis to Block Viral Entry

Samad Amini-Bavil-Olyaee, Youn Jung Choi, Jun Han Lee, Mude Shi, I-Chueh Huang, Michael Farzan and Jae U. Jung

Highlights
► 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

Summary
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.