乙型肝炎剪接蛋白（HBSP）通过激活PI3K / Akt信号传导抑制Fas介

StephenW

J Virol. 2018 Sep 12. pii: JVI.01273-18. doi: 10.1128/JVI.01273-18. [Epub ahead of print]
Hepatitis B spliced protein (HBSP) suppresses Fas-mediated hepatocyte apoptosis via activation of PI3K/Akt signaling.
Wu SX1, Chen WN1, Jing ZT1, Liu W1, Lin XJ1, Lin X2,3.
Author information

1
    Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
2
    Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China [email protected].
3
    Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.

Abstract

Hepatitis B spliced protein (HBSP) is known to associate with viral persistence and pathogenesis, however, its biological and clinical significance remains poorly defined. Acquired resistance to Fas-mediated apoptosis is thought as one of the major promotors for hepatitis B virus (HBV) chronicity and malignancy. The purpose of this study was to investigate whether HBSP could protect hepatocytes against Fas-initiated apoptosis. We showed here that HBSP mediated resistance of hepatoma cells or primary human hepatocytes (PHH) to agonistic anti-Fas antibody (CH11)- or FasL-induced apoptosis. Under Fas signaling stimulation, expression of HBSP inhibited Fas aggregation and prevented recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 (or FADD like interleukin 1 β-converting enzyme, FLICE) into the death-inducing signaling complex (DISC), while increasing recruitment of cellular FLICE-inhibitory protein L (FLIPL) into the DISC. Those effects may be mediated through activation of PI3K/AKT pathway as evidenced by increased cellular PIP3 content and PI3K activity, and enhanced phosphorylation of mTORC2 and PDPK1 as well as Akt itself. Confirmedly, inhibition of PI3K by LY294002 reversed the effect of HBSP on Fas aggregation, FLIPL expression and cellular apoptosis. These results indicate that HBSP functions to prevent hepatocytes from Fas-induced apoptosis by enhancing PI3K/Akt activity, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.Importance: Our study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The anti-apoptotic activity of HBSP is important for understanding hepatitis B pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may down-regulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that AKT is centrally involved in Fas-induced hepatocyte apoptosis and revealed interventions directed at inhibiting the activation or functional activity of AKT may be of therapeutic value in this process.

PMID:
    30209179
DOI:
    10.1128/JVI.01273-18

StephenW

J Virol。 2018年9月12日.pii：JVI.01273-18。 doi：10.1128 / JVI.01273-18。 [提前打印]
乙型肝炎剪接蛋白（HBSP）通过激活PI3K / Akt信号传导抑制Fas介导的肝细胞凋亡。
吴SX1，陈WN1，Jing ZT1，刘W1，林XJ1，林X2,3。
作者信息

1
    福建医科大学基础医学院胃肠癌教育部重点实验室，福州
2
    福建医科大学基础医学院胃肠癌教育部重点实验室，福州，中国[email protected]。
3
    福建医科大学医学微生物学系，福建省肿瘤微生物学重点实验室，福州

抽象

已知乙型肝炎病毒剪接蛋白（HBSP）与病毒持续性和发病机制相关，然而，其生物学和临床意义仍然不明确。获得对Fas介导的细胞凋亡的抗性被认为是乙型肝炎病毒（HBV）慢性和恶性肿瘤的主要启动子之一。这项研究的目的是调查HBSP是否可以保护肝细胞免受Fas诱导的细胞凋亡。我们在这里显示HBSP介导肝癌细胞或原代人肝细胞（PHH）对激动性抗Fas抗体（CH11）或FasL诱导的细胞凋亡的抗性。在Fas信号刺激下，HBSP的表达抑制Fas聚集并阻止衔接分子Fas相关死亡结构域（FADD）和procaspase-8（或FADD如白细胞介素1β转换酶，FLICE）募集到死亡诱导信号复合物中（DISC），同时增加细胞FLICE抑制蛋白L（FLIPL）募集到DISC中。这些作用可以通过激活PI3K / AKT途径介导，如通过增加的细胞PIP3含量和PI3K活性以及增强的mTORC2和PDPK1以及Akt本身的磷酸化所证明。确认，LY294002对PI3K的抑制逆转了HBSP对Fas聚集，FLIPL表达和细胞凋亡的影响。这些结果表明HBSP通过增强PI3K / Akt活性来预防肝细胞Fas诱导的细胞凋亡，这可能有助于慢性感染期间感染的肝细胞的存活和持久。重要性：我们的研究揭示了以前未被认可的HBSP在Fas-中的作用。介导的凋亡。 HBSP的抗细胞凋亡活性对于了解乙型肝炎的发病机制非常重要。特别地，与肝癌相关的HBV变体可通过增强的HBSP表达下调肝细胞的凋亡。我们的研究还发现，AKT集中参与Fas诱导的肝细胞凋亡，并且揭示了针对抑制AKT的活化或功能活性的干预可能在该过程中具有治疗价值。

结论：
    30209179
DOI：
    10.1128 / JVI.01273-18