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標題: HIV-1 Vpr運用胞器間蛋白運輸之新途徑暨 肝細胞生長因子抑制細胞凋亡之機制
A novel interorganelle protein transport pathway used by HIV-1 Vpr and the mechanism of HGF-mediated apoptosis inhibition
作者: 黃智洋
Huang, Chih-Yang
關鍵字: Vpr;粒線體;Mitochondria;ER;protein transport;lung cancer;HGF;AIF;內質網;蛋白質運輸;肺癌;肝細胞生長因子;促細胞凋亡因子
出版社: 微生物暨公共衛生學研究所
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人類免疫缺陷病毒1 (human immunodeficiency virus-1, HIV-1)屬反轉錄病毒的一種,其感染會造成人類CD4+ T細胞減少,使免疫系統出現缺陷甚或從而致命。HIV-1的輔助性蛋白質(viral protein R, Vpr) 能藉由粒線體誘發細胞凋亡,但其機制仍未明。在本論文研究,我們發現Vpr蛋白質能利用其C端之穿膜片段嵌插到內質網膜與粒線體外膜。除此之外,Vpr亦可在粒線體相關膜系(mitochondria-associated membrane , MAM)中偵測到,推測Vpr能藉由內質網經MAM運送到粒線體。而此運輸方式需要粒線體融合蛋白2 (mitofusin 2, Mfn2)、ATAD3A (AAA domain-containing 3A)和dynamin相關蛋白1 (dynamin-related protein 1, DRP1)之協助。Vpr藉由減少粒線體上Mfn2之表現,增加細胞核DRP1之表現,因此使Vpr累積在MAM影響此運輸途徑,造成粒線體蛋白減少及粒線體膜電位損傷,最終導致細胞死亡。而過度表現Mfn2與DRP1則會減少Vpr所造成之粒線體膜電位損傷及細胞死亡,因此我們推測Vpr所造成之細胞損傷主要是影響此運輸途徑,而Mfn2、 ATAD3A與DRP1則可調控此路徑。
除此之外,粒線體亦在抗病毒感染的免疫功能中扮演著重要角色。已知有某些病毒蛋白會與粒線體或其蛋白作用以誘發細胞死亡。肝細胞生長因子( hepatocyte growth factor, HGF)為多功能之生長因子,能促進細胞生長與移動及抑制細胞凋亡。HGF能藉由活化抗細胞凋亡蛋白質Bcl-2表現與抑制促細胞凋亡Bax移動到粒線體避免細胞死亡。本研究指出HGF抑制細胞凋亡主要是藉由減少AIF之表現量,而非抑制AIF轉移至核(nuclear translocation)。我們更進一步發現HGF是藉由其受體c-Met訊號傳遞途徑下游蛋白focal adhesion kinase (FAK)降低AIF之表現。將FAK基因剃除或利用突變型 FAK干擾正常FAK表現,均會增加AIF之表現量。因此我們認為HGF可能藉由其受體活化下游蛋白質FAK,並減少AIF之表現,抑制細胞凋亡。
總結而論,本研究探討 HIV-1 Vpr運送到粒線體之途徑及HGF減緩粒線體主導之細胞凋亡之機制。由結果顯示,HIV-1 Vpr藉由影響細胞內質網-粒線體間蛋白質運輸以誘發粒線體主導之細胞凋亡;另一方面HGF能藉由抑制AIF表現以減緩粒線體主導之細胞凋亡。本研究使我們較深入了解HIV-1 Vpr誘發粒線體主導細胞凋亡之機制,而此機制可能受生長因子調控,期許本研究或有助於未來HIV-1治療之發展研究。

Human immunodeficiency virus-1 (HIV-1) is a member of lentiviruses in the Retroviridae family. HIV-1 infection may lead to the depletion of CD4+ T cells, deficiency of immune system, and the subsequent fatal consequences. Viral protein R (Vpr), an HIV-1 accessory protein, induces apoptosis of CD4+ T cells via a mitochondria-associated pathway; however, the molecular mechanism of it is yet unclear. In this thesis, our results show that Vpr is integrated into the endoplasmic reticulum (ER) membrane and mitochondria outer membrane via its C-terminal transmembrane domain. In addition, Vpr can also be detected at the mitochondria-associated membrane (MAM), suggesting that Vpr is transported from the ER to the mitochondria via MAM. This transport pathway is mediated by mitofusin 2 (Mfn2), the ATPase AAA domain-containing 3A (ATAD3A), and dynamin-related protein 1 (DRP1). Vpr reduces Mfn2 expression and increases nuclear level of DRP1, leading to the accumulation of Vpr in MAM, reduction of mitochondrial proteins, and loss of mitochondrial membrane potential (MMP) that finally results in cell death. Overexpression of Mfn2 and DRP1 significantly resurrects MMP loss and alleviates Vpr-related cell death. Taken together, our results suggest that Vpr-mediated cellular damage occurs mainly by influencing protein transport from the ER, via MAM to the mitochondria, which are mediated by Mfn2, ATAD3A and DRP1.
Moreover, mitochondria play important roles in the host defense mechanism against viral infections. Certain viral proteins are known to interact with mitochondrial proteins or target directly to mitochondria to induce cell death. Hepatocyte growth factor (HGF) is a potent pleiotropic factor that can promote cell growth and mobility, and inhibit apoptosis. HGF can prevent cell death by activating Bcl-2 expression and inhibiting mitochondrial translocation of Bax protein. Our results show that HGF suppressed apoptosis by reducing apoptosis-inducing factor (AIF) expression, not by inhibiting nuclear translocation of AIF. We further identifies that HGF reduces AIF expression via c-Met receptor transduced downstream effector, focal adhesion kinase (FAK). Knockout of FAK gene or interfering FAK function by introducing dominant-negative mutants can increase AIF expression. These results suggest that HGF may suppress apoptosis by reducing mitochondrial AIF expression via c-Met and its downstream protein FAK.
In conclusion, this study elucidates the protein transport pathway of HIV-1 Vpr to mitochondria and the mechanism of HGF alleviated mitochondria-dependent apoptosis. Our results indicate that Vpr induces mitochondrial apoptosis by influencing protein transport between the ER and the mitochondria; and HGF, on the other hand, reduces mitochondria-dependent apoptosis by inhibiting AIF expression. Taken together, our study leads to a better understanding of HIV-1 Vpr-induced mitochondrial apoptosis, which could be regulated by growth factor. We expect that these informations would be useful to the future development of effective therapeutic regimens for HIV infection.
其他識別: U0005-1505201210460100
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