Liao Xinzhong, Xie Qian, Liang Minqi, Liao Qijun, Huang Bi, Zhang Shengze, Zhang Feng, Wang Liangliang, Yuan Lifang, Liu Xuejie, Wen Simin, Luo Chuming, Wang Dayan, Chen Yongkun, Luo Huanle, Shu Yuelong
School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
Signal Transduct Target Ther. 2025 Apr 23;10(1):131. doi: 10.1038/s41392-025-02227-6.
The H7N9 influenza virus poses a significant threat to human health, and the mechanism by which it infects humans remains incompletely understood. Our investigation has unveiled significant insights into the role of glucosidase alpha, neutral C (GANC) gene in human H7N9 infections. Through whole genome sequencing (WGS), we identified five low-frequency functional and heterozygous variants of GANC strongly associated with human H7N9 infections compared to healthy controls. Furthermore, we observed a reduction in mRNA and protein expression of GANC following H7N9 virus infection in vitro and in vivo. Subsequent experiments involving GANC demonstrated the promotion of H7N9 virus replication in a stable strain with GANC overexpression. Conversely, GANC knockdown exhibited the ability to restrict influenza A virus (IAV) replication, including H7N9, H9N2, and H1N1, both in vitro and in vivo. This inhibition was mediated by GANC's ability to promote the degradation of H7N9 hemagglutinin (HA). Moreover, we discovered that GANC knockdown facilitated the degradation of HA in a proteasome-dependent manner. The inhibition caused by GANC knockdown was mediated by promoting direct binding of HA with the proteasome 26S subunit, non-ATPase, 1 (PSMD1) and PSMD2. All five variants in the GANC gene reduced their ability to promote H7N9 virus replication, and also diminished the levels of GANC-induced HA protein expression. Our findings revealed a novel mechanism by which GANC inhibits the proteasome-dependent degradation of HA to promote H7N9 virus replication. These results suggest that GANC may play an important role in IAV replication.
H7N9流感病毒对人类健康构成重大威胁，其感染人类的机制仍未完全明确。我们的研究揭示了α-葡萄糖苷酶，中性C（GANC）基因在人类H7N9感染中的重要作用。通过全基因组测序（WGS），我们鉴定出与健康对照相比，GANC的五个低频功能性杂合变异体与人类H7N9感染密切相关。此外，我们观察到在体外和体内H7N9病毒感染后，GANC的mRNA和蛋白质表达均降低。随后涉及GANC的实验表明，在过表达GANC的稳定株中，H7N9病毒复制得到促进。相反，敲低GANC在体外和体内均表现出限制甲型流感病毒（IAV）复制的能力，包括H7N9、H9N2和H1N1。这种抑制作用是由GANC促进H7N9血凝素（HA）降解的能力介导的。此外，我们发现敲低GANC以蛋白酶体依赖性方式促进HA的降解。敲低GANC引起的抑制作用是通过促进HA与蛋白酶体26S亚基非ATP酶1（PSMD1）和PSMD2的直接结合介导的。GANC基因中的所有五个变异体均降低了其促进H7N9病毒复制的能力，同时也降低了GANC诱导的HA蛋白表达水平。我们的研究结果揭示了一种新机制，即GANC抑制蛋白酶体依赖性HA降解以促进H7N9病毒复制。这些结果表明，GANC可能在IAV复制中发挥重要作用。
