The role of phosphatidylinositol 4-kinases and phosphatidylinositol 4-phosphate during viral replication

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• 作者：Leen Delang ; Jan Paeshuyse ; Johan Neyts ; ^{Johan.Neyts@rega.kuleuven.be}
• 关键词：PI4KIII¦Á ; PI4KIII¦Â ; PI4P ; Viral replication ; Antiviral target
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 出版时间：1 December, 2012
• 年：2012
• 卷：84
• 期：11
• 页码：1400-1408
• 全文大小：763 K

文摘

Phosphoinositides (PI) are phospholipids that mediate signaling cascades in the cell by binding to effector proteins. Reversible phosphorylation of the inositol ring at positions 3, 4 and 5 results in the synthesis of seven different phosphoinositides. Each phosphoinositide has a unique subcellular distribution with a predominant localization in subsets of membranes. These lipids play a major role in recruiting and regulating the function of proteins at membrane interfaces . Several bacteria and viruses modulate and exploit the host PI metabolism to ensure efficient replication and survival. Here, we focus on the roles of cellular phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4-kinases (PI4Ks) during the replication cycle of various viruses. It has been well documented that phosphatidylinositol 4-kinase III¦Â (PI4KIII¦Â, EC 2.7.1.67) is indispensable for viral RNA replication of several picornaviruses. Two recruitment strategies were reported: (i) binding and modulation of GBF1/Arf1 to enhance recruitment of PI4KIII¦Â and (ii) interaction with ACBD3 for recruitment of PI4KIII¦Â. PI4KIII has also been demonstrated to be crucial for hepatitis C virus (HCV) replication. PI4KIII appears to be directly recruited and activated by HCV NS5A protein to the replication complexes. In contrast to picornaviruses, it is still debated whether the ¦Á or the ¦Â isoform is the most important. PI4KIII can be explored as a target for inhibition of viral replication. The challenge will be to develop highly selective inhibitors for PI4KIII¦Á and/or ¦Â and to avoid off-target toxicity.