129 MODULATION OF PHOSPHORYLATION OF HEPATITIS C VIRUS NONSTRUCTURAL PROTEIN 5A BY THE LIPID KINASE PI4KIIIα

Reiss, Simon; Harak, Christian; Romero-Brey, Inés; Rebhan, Ilka; Radujkovic, Danijela; Bartenschlager, Ralf; Lohmann, Volker

doi:10.1016/s0168-8278(12)60143-3

Cited by 1 publication

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“…Further studies are therefore required to determine the importance of PI4P accumulation at the HCV replication complexes. Another recent hypothesis is that PI4KIIIa influences the modulation of HCV NS5A phosphorylation, by supporting p56 synthesis and thereby stimulating RNA replication [49] (Fig. 2).…”

Section: Authorsmentioning

confidence: 96%

“…This interaction occurs between domain I of NS5A and amino acids 400-600 of PI4KIIIa [48]. More recently, the required NS5A amino acids for interaction with PI4KIIIa were assigned to the C-terminal end of domain I [49]. The enzymatic activity of the lipid kinase is required for HCV replication, as shown by rescue experiments in PI4KIIIa knockdown cell lines with wild-type or a kinase-dead mutant of the enzyme [41].…”

Section: The Role Of Pi4ks In the Life Cycle Of Hepatitis C Virusmentioning

confidence: 99%

“…Loss of PI4KIIIa interaction and RNA replication correlated with increased levels of p58, suggesting that PI4KIIIa might be involved in the regulation of NS5A phosphorylation. Overexpression and knockdown of PI4KIIIa resulted in relatively increased or decreased portions of NS5A p56 , respectively [49]. It remains to be elucidated whether NS5A phosphorylation is directly or indirectly modulated by PI4KIIIa.…”

Section: Authorsmentioning

confidence: 99%

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

Delang

Paeshuyse

Neyts

2012

Biochemical Pharmacology

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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 [1]. 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 IIIβ (PI4KIIIβ, 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 PI4KIIIβ and (ii) interaction with ACBD3 for recruitment of PI4KIIIβ. 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 α or the β 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 PI4KIIIα and/or β and to avoid off-target toxicity.

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Section: Authorsmentioning

confidence: 96%