Enteroviruses Harness the Cellular Endocytic Machinery to Remodel the Host Cell Cholesterol Landscape for Effective Viral Replication

Olha Ilnytska, Marianita Santiana, Nai-Yun Hsu, Wen-Li Du, Ying-Han Chen, Ekaterina G. Viktorova, Georgy Belov, Anita Brinker, Judith Storch, Christopher Moore, Joseph L. Dixon, and NihalAltan-Bonnet. Cell Host & Microbe, 14, 281-293 (2013)

Speaker: Chung-Lin Li (利宗霖)                   Time: 14:10~15:00, Nov. 20, 2013.

Commentator: Dr. Shun-hua Chen (陳舜華老師)      Place: Room 601

Abstract:

Enteroviruses are a genus of positive-sense single-stranded RNA viruses which include many important human pathogens such as poliovirus, Coxsackievirus, human rhinovirus, enterovirusand echovirus. Many RNA viruses, including enteroviruses, use membrane as platforms on which viral replication machinery is assembled and genomes are replicated (1). These membranes utilized for replication are so called “replication organelles.” Previous studies have focused on the role of cholesterols in regulating viral attachment and viral entry and in mediating signaling for antiviral immune responses (2). In this study, the authors found that clathrin-mediated endocytosis (CME) plays an important role in trafficking cholesterol from plasma membrane (PM) and extracellular medium to replication organelles. Using siRNA to knockdown the genes which have established roles in CME significantly inhibited both Coxsackievirus B3 and poliovirus replication and disrupted the biogenesis of replication organelle. In addition, viral replication and replication organelle biogenesis were inhibited when the authors further depleted PM-free cholesterol pools by treating cells with methyl-β cyclodextrin (MβCD). The replication was rescued when adding back cholesterol. The authors next investigated how cholesterol was targeted to replication organelles. Time-lapse microscopy revealed numerous Rab11 recycling endosomes could traffick to replication organelles. Moreover, enterovirus 3A protein could utilize Rab11 to target cholesterol to replication organelles and prevent it from cycling back to the PM. These findings may provide new therapeutic strategies for treating enteroviral infections including blocking cholesterol uptake or biosynthesis, stimulating cholesterol storage, and preventing cholesterol from being trafficked to replication organelles by disrupting the viral recruitment of Rab11 proteins.

References:

1.     McCloskey, M.A., and Poo, M.M. (1986). Rates of membrane-associated reactions: reduction of dimensionality revisited. J. Cell Biol. 102, 88–96.

2.     Howes, M.T., Mayor, S., and Parton, R.G. (2010). Molecules, mechanisms, and cellular roles of clathrin-independent endocytosis. Curr. Opin. Cell Biol. 22, 519–527.