Bay41-4109 诱导的乙型肝炎衣壳蛋白异常聚合物通过 STUB1 促进

StephenW

Bay41-4109 诱导的乙型肝炎衣壳蛋白异常聚合物通过 STUB1 促进的 p62 介导的巨自噬被去除
林家成 1 2 , 尹立民 1 , 徐夏珍 1 , 孙和臣 1 , 黄志华 1 , 倪雪云 1 , 陈彦 1 2 , 许琳 1 2
隶属关系
隶属关系

    1
    胃肠癌教育部重点实验室（福建医科大学），福州，中国。
    2
    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。

    PMID：35030230 DOI：10.1371/journal.ppat.1010204

抽象的

乙型肝炎病毒 (HBV) 核心蛋白 (HBc) 在病毒生命周期的多个步骤中发挥作用。 Bay41-4109 等杂芳基二氢嘧啶化合物 (HAP) 是衣壳蛋白变构调节剂，可加速 HBc 降解并抑制 HBV 病毒粒子的分泌，特别是通过误导 HBc 组装成异常的非衣壳聚合物。然而，这些 HAP 诱导的异常非衣壳聚合物随后的细胞命运尚不清楚。在这里，我们发现伴侣结合 E3 泛素连接酶蛋白 STUB1 是从 HepAD38 细胞中去除 Bay41-4109 诱导的异常非衣壳聚合物所必需的。具体来说，STUB1 募集 BAG3 将 Bay41-4109 诱导的异常非衣壳聚合物转运到细胞的核周区域，从而启动 p62 介导的巨自噬和溶酶体降解。我们还证明，提高 STUB1 水平可增强 Bay41-4109 对 HepAD38 细胞、HBV 感染的 HepG2-NTCP 细胞和 HBV 转基因小鼠中 HBeAg 和 HBV 病毒粒子产生的抑制作用。 STUB1 过表达还促进了 Bay41-4109 对 HBV 从头感染中 cccDNA 形成的抑制。了解这些分子细节为将 HAP 作为一种潜在的治疗方案（或联合治疗的一个组成部分）从慢性感染患者的肝细胞中根除 HBV 铺平了道路。

StephenW

Bay41-4109-induced aberrant polymers of hepatitis b capsid proteins are removed via STUB1-promoted p62-mediated macroautophagy
Jiacheng Lin  1   2 , Limin Yin  1 , Xia-Zhen Xu  1 , He-Chen Sun  1 , Zhi-Hua Huang  1 , Xue-Yun Ni  1 , Yan Chen  1   2 , Xu Lin  1   2
Affiliations
Affiliations

    1
    Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
    2
    Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.

    PMID: 35030230 DOI: 10.1371/journal.ppat.1010204

Abstract

The hepatitis B virus (HBV) core protein (HBc) functions in multiple steps of the viral life cycle. Heteroaryldihydropyrimidine compounds (HAPs) such as Bay41-4109 are capsid protein allosteric modulators that accelerate HBc degradation and inhibit the virion secretion of HBV, specifically by misleading HBc assembly into aberrant non-capsid polymers. However, the subsequent cellular fates of these HAP-induced aberrant non-capsid polymers are not well understood. Here, we discovered that that the chaperone-binding E3 ubiquitin ligase protein STUB1 is required for the removal of Bay41-4109-induced aberrant non-capsid polymers from HepAD38 cells. Specifically, STUB1 recruits BAG3 to transport Bay41-4109-induced aberrant non-capsid polymers to the perinuclear region of cells, thereby initiating p62-mediated macroautophagy and lysosomal degradation. We also demonstrate that elevating the STUB1 level enhances the inhibitory effect of Bay41-4109 on the production of HBeAg and HBV virions in HepAD38 cells, in HBV-infected HepG2-NTCP cells, and in HBV transgenic mice. STUB1 overexpression also facilitates the inhibition of Bay41-4109 on the cccDNA formation in de novo infection of HBV. Understanding these molecular details paves the way for applying HAPs as a potentially curative regimen (or a component of a combination treatment) for eradicating HBV from hepatocytes of chronic infection patients.

StephenW

https://journals.plos.org/plospa ... &type=printable