研究人員發(fā)現(xiàn)一種新蛋白能夠阻止丙肝病毒的復(fù)制,，這一發(fā)現(xiàn)將可能為丙肝新藥的設(shè)計提供重要線索。
丙肝是一種血液攜帶的傳染疾病,，能夠?qū)е赂窝?、肝硬化和肝癌。這種病毒通過復(fù)制自己的RNA在寄住體內(nèi)傳播,，并利用RNA制造蛋白質(zhì),、形成新病毒并抑制寄住細(xì)胞中不同的抗病毒蛋白質(zhì)。
通過了解這兩種機(jī)制,，研究人員希望能夠阻止病毒復(fù)制,，進(jìn)而終止感染。Stanley M. Lemon和同事發(fā)現(xiàn)一種新蛋白與終止這種病毒復(fù)制有個,。這種蛋白質(zhì)叫做p21活化激酶I,，該蛋白在若干細(xì)胞信號途徑中起到一定的作用，但之前并未證實與調(diào)節(jié)丙肝病毒的復(fù)制有關(guān),。
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
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.
