乙型肝炎病毒小包膜蛋白中的假定两亲性α螺旋在亚病毒颗

StephenW

A Putative Amphipathic Alpha Helix in Hepatitis B Virus Small Envelope Protein Plays a Critical Role in the Morphogenesis of Subviral Particles
Sisi Yang, Zhongliang Shen, Yaoyue Kang, Liren Sun, Usha Viswanathan, Hongying Guo, Tianlun Zhou, Xinghong Dai, Jinhong Chang, Jiming Zhang, Ju-Tao Guo
J.-H. James Ou, Editor
DOI: 10.1128/JVI.02399-20

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ABSTRACT

Hepatitis B virus (HBV) small (S) envelope protein has the intrinsic ability to direct the formation of small spherical subviral particles (SVPs) in eukaryotic cells. However, the molecular mechanism underlying the morphogenesis of SVPs from the monomeric S protein initially synthesized at the endoplasmic reticulum (ER) membrane remains largely elusive. Structure prediction and extensive mutagenesis analysis suggested that the amino acid residues spanning W156 to R169 of S protein form an amphipathic alpha helix and play essential roles in SVP production and S protein metabolic stability. Further biochemical analyses showed that the putative amphipathic alpha helix was not required for the disulfide-linked S protein oligomerization but was essential for SVP morphogenesis. Pharmacological disruption of vesicle trafficking between the ER and Golgi complex in SVP-producing cells supported the hypothesis that S protein-directed SVP morphogenesis takes place at the ER-Golgi intermediate compartment (ERGIC). Moreover, it was demonstrated that S protein is degraded in hepatocytes via a 20S proteasome-dependent but ubiquitination-independent nonclassic ER-associated degradation pathway. Taken together, the results reported here favor a model in which the amphipathic alpha helix at the antigenic loop of S protein attaches to the lumen leaflet to facilitate SVP budding from the ERGIC, whereas the failure of the budding process may result in S protein degradation by 20S proteasome in a ubiquitination-independent manner.

IMPORTANCE SVPs are the predominant viral product produced by HBV-infected hepatocytes. Their levels exceed those of virion particles by 10,000- to 100,000-fold in the blood of HBV-infected individuals. The high levels of SVPs, or HBV surface antigen (HBsAg), in the circulation induce immune tolerance and contribute to the establishment of persistent HBV infection. The loss of HBsAg, often accompanied by the appearance of anti-HBsAg antibodies, is the hallmark of durable immune control of HBV infection. Therapeutic induction of HBsAg loss is thus considered to be essential for the restoration of the host antiviral immune response and functional cure of chronic hepatitis B. Our findings on the mechanism of SVP morphogenesis and S protein metabolism will facilitate the rational discovery and development of antiviral drugs to achieve this therapeutic goal.

    Copyright © 2021 American Society for Microbiology.

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StephenW

乙型肝炎病毒小包膜蛋白中的假定两亲性α螺旋在亚病毒颗粒的形态发生中起关键作用
杨思思，沉忠良，康耀跃，孙立人，Usha Viswanathan，郭宏颖，周天伦，戴兴宏，张金宏，张继明，郭菊涛
J.-H.欧文（James Ou），编辑
DOI：10.1128 / JVI.02399-20

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抽象的

乙型肝炎病毒（HBV）小（S）包膜蛋白具有指导真核细胞中小的球形亚病毒颗粒（SVP）形成的内在能力。但是，从最初在内质网（ER）膜上合成的单体S蛋白形成SVP的分子机制尚不清楚。结构预测和广泛的诱变分析表明，跨越S蛋白的W156至R169的氨基酸残基形成两亲性α螺旋，并在SVP产生和S蛋白代谢稳定性中起重要作用。进一步的生化分析表明，二硫键连接的S蛋白低聚不需要推定的两亲性α螺旋，但对于SVP形态发生是必不可少的。产生SVP的细胞中ER和高尔基复合体之间的小泡运输的药理学破坏支持了S蛋白指导的SVP形态发生在ER-高尔基体中隔室（ERGIC）的假说。此外，已证明S蛋白通过20S蛋白酶体依赖性但不与泛素化无关的非经典ER相关的降解途径在肝细胞中降解。综上所述，这里报道的结果支持一种模型，其中S蛋白抗原环上的两亲性α螺旋附着在管腔小叶上，以促进SVP从ERGIC出芽，而出芽过程的失败可能导致S蛋白降解。 20S蛋白酶体以泛素化无关的方式。

重要说明SVP是HBV感染的肝细胞产生的主要病毒产物。在被HBV感染的人的血液中，它们的水平超过病毒颗粒的水平10,000到100,000倍。循环中高水平的SVP或HBV表面抗原（HBsAg）诱导免疫耐受并有助于建立持久性HBV感染。 HBsAg的丢失通常伴随着抗HBsAg抗体的出现，是对HBV感染进行持久免疫控制的标志。因此，治疗性诱导HBsAg丢失对于恢复宿主抗病毒免疫应答和慢性乙型肝炎的功能治愈至关重要。我们对SVP形态发生和S蛋白代谢机制的研究发现将有助于合理发现和开发抗病毒药物达到这个治疗目的。

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