Liu Yu, Yang Jiaxin, Wang Yanyan, Zeng Qiqi, Fan Yao, Huang Ailong, Fan Hui
The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
Genes Dis. 2023 Oct 14;11(6):101142. doi: 10.1016/j.gendis.2023.101142. eCollection 2024 Nov.
Chronic hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma, representing a global health problem for which a functional cure is difficult to achieve. The HBV core protein (HBc) is essential for multiple steps in the viral life cycle. It is the building block of the nucleocapsid in which viral DNA reverse transcription occurs, and its mediation role in viral-host cell interactions is critical to HBV infection persistence. However, systematic studies targeting HBc-interacting proteins remain lacking. Here, we combined HBc with the APEX2 to systematically identify HBc-related host proteins in living cells. Using functional screening, we confirmed that proteasome activator subunit 1 (PSME1) is a potent HBV-associated host factor. PSME1 expression was up-regulated upon HBV infection, and the protein level of HBc decreased after PSME1 knockdown. Mechanistically, the interaction between PSME1 and HBc inhibited the degradation of HBc by the 26S proteasome, thereby improving the stability of the HBc protein. Furthermore, PSME1 silencing inhibits HBV transcription in the HBV infection system. Our findings reveal an important mechanism by which PSME1 regulates HBc proteins and may facilitate the development of new antiviral therapies targeting PSME1 function.
慢性乙型肝炎病毒（HBV）感染是肝硬化和肝细胞癌的主要原因，是一个难以实现功能性治愈的全球健康问题。HBV核心蛋白（HBc）在病毒生命周期的多个步骤中至关重要。它是病毒DNA逆转录发生的核衣壳的组成部分，其在病毒-宿主细胞相互作用中的介导作用对于HBV感染的持续存在至关重要。然而，针对与HBc相互作用蛋白的系统性研究仍然缺乏。在此，我们将HBc与APEX2结合，以系统性地鉴定活细胞中与HBc相关的宿主蛋白。通过功能筛选，我们证实蛋白酶体激活亚基1（PSME1）是一种有效的HBV相关宿主因子。HBV感染后PSME1表达上调，PSME1敲低后HBc蛋白水平降低。机制上，PSME1与HBc之间的相互作用抑制了26S蛋白酶体对HBc的降解，从而提高了HBc蛋白的稳定性。此外，PSME1沉默抑制了HBV感染系统中的HBV转录。我们的研究结果揭示了PSME1调节HBc蛋白的重要机制，并可能促进针对PSME1功能的新型抗病毒疗法的开发。
