TRIM21 通过 SQSTM1-NRF2-KEAP1 轴促进氧化应激和铁死亡，从而提高 H5N1 高致病性禽流感病毒滴度。

TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus.

机构信息

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.

Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China.

出版信息

Int J Mol Sci. 2024 Mar 14;25(6):3315. doi: 10.3390/ijms25063315.

DOI:10.3390/ijms25063315

PMID:38542289

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10970474/

Abstract

Tripartite motif-containing protein 21 (TRIM21) is involved in signal transduction and antiviral responses through the ubiquitination of protein targets. TRIM21 was reported to be related to the imbalance of host cell homeostasis caused by viral infection. Our studies indicated that H5N1 highly pathogenic avian influenza virus (HPAIV) infection up-regulated TRIM21 expression in A549 cells. Western blot and qPCR results showed that knockdown of TRIM21 alleviated oxidative stress and ferroptosis induced by H5N1 HPAIV and promoted the activation of antioxidant pathways. Co-IP results showed that TRIM21 promoted oxidative stress and ferroptosis by regulating the SQSTM1-NRF2-KEAP1 axis by increasing SQSTM1 K63-linked polyubiquitination under the condition of HPAIV infection. In addition, TRIM21 attenuated the inhibitory effect of antioxidant NAC on HPAIV titers and enhanced the promoting effect of ferroptosis agonist Erastin on HPAIV titers. Our findings provide new insight into the role of TRIM21 in oxidative stress and ferroptosis induced by viral infection.

摘要

三结构域蛋白 21（TRIM21）通过蛋白质靶标的泛素化参与信号转导和抗病毒反应。有报道称，TRIM21与病毒感染引起的宿主细胞内环境失衡有关。我们的研究表明，H5N1 高致病性禽流感病毒（HPAIV）感染可上调 A549 细胞中 TRIM21 的表达。Western blot 和 qPCR 结果表明，TRIM21 的敲低可减轻 H5N1 HPAIV 诱导的氧化应激和铁死亡，并促进抗氧化途径的激活。Co-IP 结果表明，TRIM21 通过增加 SQSTM1 K63 连接的多泛素化，在 HPAIV 感染条件下，调节 SQSTM1-NRF2-KEAP1 轴，从而促进氧化应激和铁死亡。此外，TRIM21 减弱了抗氧化剂 NAC 对 HPAIV 滴度的抑制作用，并增强了铁死亡激动剂 Erastin 对 HPAIV 滴度的促进作用。我们的研究结果为 TRIM21 在病毒感染诱导的氧化应激和铁死亡中的作用提供了新的见解。