Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
BMC Med. 2024 Nov 7;22(1):521. doi: 10.1186/s12916-024-03724-1.
Hepatitis B virus (HBV) is an enveloped DNA virus that causes chronic hepatitis B (CHB) infection. Annexin, a Ca-activated protein, is widely expressed in various organs and tissues and has potential utility in disease diagnosis and treatment. However, the relationship between the annexin family and CHB remains unclear.
Clinical samples from hepatitis patients and donors or healthy individuals were collected. Transcriptome sequencing in CHB liver tissues and HBV-infected cells were performed. HepG2.2.15 cells with the full-length HBV genome and HBV-infected HepG2-NTCP cell models were established. HBV-infected mouse model was constructed and adeno-associated virus was utilized.
ANXA4 expression was elevated during CHB infection. ANXA4 knockdown promoted HBV replication and aggravated liver injury, while ANXA4 overexpression alleviated that. Mechanistically, autophagy pathway was activated by ANXA4 deficiency, promoting autophagic degradation of minichromosome maintenance complex component 2 (MCM2). MCM2 inhibition activated HBV replication, while MCM2 overexpression attenuated ANXA4 deficiency-induced HBV replication and liver injury. Clinically, the expression of hepatitis B viral protein was negatively correlated with the ANXA4 levels, and CHB patients with high ANXA4 levels (> 8 ng/ml) showed higher sensitivity to interferon therapy.
ANXA4 functions as a protective factor during HBV infection. ANXA4 expression is elevated under HBV attack to restrict HBV replication by inhibiting autophagic degradation of MCM2, thereby alleviating liver injury and suppressing the CHB infection process. ANXA4 also enhances the sensitivity of CHB patients to interferon therapy. Therefore, ANXA4 is expected to be a new target for CHB treatment and prognostic evaluation.
乙型肝炎病毒（HBV）是一种包膜 DNA 病毒，可导致慢性乙型肝炎（CHB）感染。膜联蛋白是一种 Ca 激活蛋白，广泛表达于各种器官和组织中，在疾病的诊断和治疗中有潜在的应用价值。然而，膜联蛋白家族与 CHB 的关系尚不清楚。
收集了肝炎患者和供体或健康个体的临床样本。对 CHB 肝组织和 HBV 感染细胞进行了转录组测序。建立了含有完整 HBV 基因组的 HepG2.2.15 细胞和 HBV 感染的 HepG2-NTCP 细胞模型。构建了 HBV 感染的小鼠模型，并利用腺相关病毒。
在 CHB 感染过程中，ANXA4 的表达上调。ANXA4 敲低促进 HBV 复制并加重肝损伤，而 ANXA4 过表达则减轻了这种情况。机制上，ANXA4 缺乏激活自噬途径，促进微小染色体维持复合物成分 2（MCM2）的自噬降解。MCM2 抑制激活 HBV 复制，而 MCM2 过表达则减弱了 ANXA4 缺乏诱导的 HBV 复制和肝损伤。临床上，乙型肝炎病毒蛋白的表达与 ANXA4 水平呈负相关，HBV 水平较高（>8ng/ml）的 CHB 患者对干扰素治疗更敏感。
ANXA4 在 HBV 感染过程中起保护作用。在 HBV 攻击下，ANXA4 的表达上调，通过抑制 MCM2 的自噬降解来限制 HBV 复制，从而减轻肝损伤并抑制 CHB 感染过程。ANXA4 还提高了 CHB 患者对干扰素治疗的敏感性。因此，ANXA4 有望成为 CHB 治疗和预后评估的新靶点。
