研究人員最近發(fā)現(xiàn)一種抑制丙型肝炎病毒復(fù)制的蛋白,，為研發(fā)治療丙型肝炎的新藥提供了參考,。
丙型肝炎是一種血源性傳染病，有引發(fā)肝硬化和肝癌的可能,。病毒通過復(fù)制和抑制宿主體內(nèi)各種抗病毒蛋白,，在宿主體內(nèi)傳播。研究人員希望弄清這兩個機制,，抑制病毒復(fù)制,、停止病毒傳播。
p21-活化蛋白激酶1（p21-activated kinase 1）是一種在許多細胞信號傳遞途徑中扮演重要角色的蛋白,，以前人們不知道其與調(diào)節(jié)丙型肝炎復(fù)制有關(guān),。Stanley M. Lemon等最近發(fā)現(xiàn)，這種蛋白能夠抑制病毒復(fù)制,。
原始出處:
J. Biol. Chem., Vol. 282, Issue 16, 11836-11848, April 20, 2007
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*
Hisashi Ishida, Kui Li, MinKyung Yi, and Stanley M. Lemon1
From the Center for Hepatitis Research, Institute for Human Infections and Immunity, and the Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1018
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.
