Kazemi Shirin, Papadopoulou Stavroula, Li Suiyang, Su Qiaozhu, Wang Shuo, Yoshimura Akihiko, Matlashewski Greg, Dever Thomas E, Koromilas Antonis E
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec H3T 1E2, Canada.
Mol Cell Biol. 2004 Apr;24(8):3415-29. doi: 10.1128/MCB.24.8.3415-3429.2004.
Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2alpha phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2alpha phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2alpha dephosphorylation. Inhibition of eIF2alpha phosphorylation by E6 mitigates eIF2alpha-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2alpha phosphorylation. The functional interaction between E6 and the eIF2alpha phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.
真核生物翻译起始因子2（eIF2α）的α亚基在丝氨酸51位点的磷酸化会抑制遭受包括病毒感染在内的各种应激形式的细胞中的蛋白质合成。人乳头瘤病毒（HPV）E6癌蛋白通过多种机制导致病毒诱导的致病性，包括抑制细胞凋亡和阻断干扰素（IFN）作用。我们通过干扰素诱导蛋白激酶PKR的诱导二聚化形式研究了E6癌蛋白与eIF2α磷酸化之间可能的功能关系。在此，我们证明，激酶的条件激活导致eIF2α磷酸化后，18型HPV E6蛋白的合成迅速受到抑制。然而，E6的其余部分可以使细胞免受PKR介导的蛋白质合成抑制和细胞凋亡诱导。E6与介导翻译恢复的GADD34/PP1全磷酸酶复合物发生物理结合，并促进eIF2α去磷酸化。E6对eIF2α磷酸化的抑制减轻了eIF2α对促凋亡基因转录和翻译的依赖性反应。这些发现首次证明了致癌性E6在PKR和eIF2α磷酸化诱导的凋亡信号传导中的作用。E6与eIF2α磷酸化途径之间的功能相互作用可能对HPV感染和相关发病机制具有重要意义。
