p21-activated Kinase 1 Is Activated through the Mammalian Target of Rapamycin/p70 S6 Kinase Pathway and Regulates the Replication of Hepatitis C Virus in Human Hepatoma Cells

Abstract

Cellular mechanisms that regulate the replication of hepatitis C virus (HCV) RNA are poorly understood. p21-activated kinase 1 (PAK1) is a serine/threonine kinase that has been suggested to participate in antiviral signaling. We studied its role in the cellular control of HCV replication. Transfection of PAK1-specific small interfering RNA enhanced viral RNA and protein abundance in established replicon cell lines as well as cells infected with chimeric genotype 1a/2a HCV, despite reducing cellular proliferation, suggesting specific regulation of HCV replication. PAK1 knockdown did not reduce interferon regulatory factor 3-dependent gene expression, indicating that this regulation is independent of the retinoic acid-inducible gene I/interferon regulatory factor 3 pathway. On the other hand, LY294002 and rapamycin abolished PAK1 phosphorylation and enhanced HCV abundance, suggesting that the mammalian target of rapamycin (mTOR) is involved in PAK1 regulation of HCV. Small interfering RNA knockdown of the mTOR substrate p70 S6 kinase abrogated PAK1 phosphorylation and enhanced HCV RNA abundance, whereas overexpression of a constitutively active alternate substrate, eukaryotic translation initiation factor 4E-binding protein 1, increased cap-independent viral translation and viral RNA abundance without influencing PAK1 phosphorylation. Similar data indicated that mTOR is regulated by both phosphatidylinositol 3-kinase/Akt and ERK. Taken together, the data indicate that p70 S6 kinase activates PAK1 and contributes to phosphatidylinositol 3-kinase-and ERK-mediated regulation of HCV RNA replication.

Suppressor of Cytokine Signaling 3 Suppresses Hepatitis C Virus Replication in an mTOR-Dependent Manner

“…NRas-mediated PI3K activation results in mTOR activation, and when mTOR is knocked down, HCV abundance is enhanced (15). Ishida et al also found HCV RNA replication to be suppressed by the mTOR substrate P70 S6K (9). Thus, the evidence supports the possibility that activation of the mTOR signaling pathway suppresses HCV replication.…”

Rho’ing in and out of cells

“…The mTOR downstream effector p70S6 kinase activates PAK1 and contributes to PI3K-and ERK-mediated inhibition of HCV RNA replication. 108 Viruses typically need full viral gene expression and a resulting productive viral replication at some point to spread to other hosts. However, some viruses also benefit from a stealth mechanism with very limited viral gene expression.…”

Molecular mechanisms of insulin resistance in chronic hepatitis C

“…Interestingly, IR has been associated in several studies with elevated HCV viral loads [28,41,42] . One possible mechanism involves p21-activated kinase 1, which suppresses HCV replication and is stimulated by PI3K/Akt signaling, via mTOR [43] . HCV-associated IR could decrease PI3K/Akt signaling and thus favor viral replication, although the mechanism by which HCV induces IR is unclear.…”