Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
Department of Orthopedics, Peking University Third Hospital, 49 North Garden Road, Beijing, 100191, China.
Cell Death Dis. 2023 Dec 21;14(12):855. doi: 10.1038/s41419-023-06379-7.
The E3 ubiquitin ligase RING finger protein 115 (RNF115), also known as breast cancer-associated gene 2 (BCA2), has been linked with the growth of some cancers and immune regulation, which is negatively correlated with prognosis. Here, it is demonstrated that the RNF115 deletion can protect mice from acute liver injury (ALI) induced by the treatment of lipopolysaccharide (LPS)/D-galactosamine (D-GalN), as evidenced by decreased levels of alanine aminotransaminase, aspartate transaminase, inflammatory cytokines (e.g., tumor necrosis factor α and interleukin-6), chemokines (e.g., MCP1/CCL2) and inflammatory cell (e.g., monocytes and neutrophils) infiltration. Moreover, it was found that the autophagy activity in Rnf115 livers was increased, which resulted in the removal of damaged mitochondria and hepatocyte apoptosis. However, the administration of adeno-associated virus Rnf115 or autophagy inhibitor 3-MA impaired autophagy and aggravated liver injury in Rnf115 mice with ALI. Further experiments proved that RNF115 interacts with LC3B, downregulates LC3B protein levels and cell autophagy. Additionally, Rnf115 deletion inhibited M1 type macrophage activation via NF-κB and Jnk signaling pathways. Elimination of macrophages narrowed the difference in liver damage between Rnf115 and Rnf115 mice, indicating that macrophages were linked in the ALI induced by LPS/D-GalN. Collectively, for the first time, we have proved that Rnf115 inactivation ameliorated LPS/D-GalN-induced ALI in mice by promoting autophagy and attenuating inflammatory responses. This study provides new evidence for the involvement of autophagy mechanisms in the protection against acute liver injury.
E3 泛素连接酶 RING 指蛋白 115（RNF115），也称为乳腺癌相关基因 2（BCA2），与一些癌症的生长和免疫调节有关，与预后呈负相关。在这里，研究表明 RNF115 的缺失可以保护小鼠免受脂多糖（LPS）/D-半乳糖胺（D-GalN）诱导的急性肝损伤（ALI），其依据是丙氨酸氨基转移酶、天冬氨酸氨基转移酶、炎症细胞因子（如肿瘤坏死因子 α 和白细胞介素-6）、趋化因子（如 MCP1/CCL2）和炎症细胞（如单核细胞和中性粒细胞）的水平降低。此外，研究发现 Rnf115 肝脏中的自噬活性增加，导致损伤的线粒体和肝细胞凋亡被清除。然而，腺相关病毒 Rnf115 的给药或自噬抑制剂 3-MA 会损害自噬并加重 Rnf115 小鼠的 ALI。进一步的实验证明，RNF115 与 LC3B 相互作用，下调 LC3B 蛋白水平和细胞自噬。此外，Rnf115 的缺失通过 NF-κB 和 Jnk 信号通路抑制 M1 型巨噬细胞的激活。巨噬细胞的消除缩小了 Rnf115 和 Rnf115 小鼠之间肝损伤的差异，表明巨噬细胞参与了 LPS/D-GalN 诱导的 ALI。总之，我们首次证明 Rnf115 的失活通过促进自噬和减弱炎症反应，改善了 LPS/D-GalN 诱导的小鼠 ALI。该研究为自噬机制在急性肝损伤保护中的作用提供了新的证据。
