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. Cell Host & Microbe, 2013. 13, 452-464

Speaker: Yu-Rou Liao (廖毓柔)                                     Time: 15:10~16:00, May 7, 2014

Commentator: Dr. Pin Ling (凌斌 老師)            Place: Room 601

Abstract:

Enveloped viruses enter the cell through endocytosis, followed by membrane fusion with endosome or lysosome to release nucleocapsid and genome to cytosol. Interferon-inducible transmembrane protein 3 (IFITM3) has been proved to inhibit the entry of several enveloped viruses, including vesicular stomatitis virus and influenza A virus. In the present study, the authors aimed to address the mechanism mediated by IFITM3 to inhibit virus entry. Using yeast two hybrid screening, they found that IFITM3 interacted with vesicle-membrane-protein-associated protein A (VAPA) to exert its antiviral response. Under normal physiological conditions, VAPA interacts with oxysterol-binding protein (OSBP) to regulate intracellular cholesterol homeostasis¹. During virus infection, IFITM3 bound to VAPA and blocked the interaction of VAPA and OSBP, which resulted in accumulation of cholesterol in endosomal compartments and reduced viral entry and replication of vesicular stomatitis virus and influenza A virus ^2,3. Blocking the interaction of IFITM3 with VAPA via modifying the transmembrane domain of IFITM3, they found that the numbers of cholesterol-laden endosomes were reduced, and the numbers of virus-infected cells were significantly increased. In conclusion, the present study demonstrates that IFITM3 interacts with VAPA to disturb intracellular cholesterol transportation, resulting in the accumulation of cholesterol in endosomal compartments. The cholesterol-laden endosomal compartments block the fusion between intraluminal vesicles and late endosome membrane. These findings reveal the antiviral mechanism of IFITM3, which provides a potential therapy to target virus-containing vesicles for defense against viral infection.

References:

1         Raychaudhuri, S. & Prinz, W. A. The diverse functions of oxysterol-binding proteins. Annual Review of Cell and Developmental Biology, 26: 157 (2010).

2          Bailey, C. C., Huang, I. C., Kam, C. & Farzan, M. Ifitm3 limits the severity of acute influenza in mice. PLoS Pathogens 8: e1002909 (2012).

3          Weidner, J. M. et al. Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. Journal of Virology 84: 12646 (2010).