Wang Yuanyuan, Sun Hui, Liu Yuxin, Song Yanjun, Wang Weitong, Li Guoli, Zhang Jie, Zhang Yuanyuan, Chen Danying, Zhao Xuesen
National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Viral Infectious Disease, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
J Med Virol. 2025 Jul;97(7):e70439. doi: 10.1002/jmv.70439.
Transmembrane protein 106B (TMEM106B) has been identified as a functional receptor facilitating ACE2-independent SARS-CoV-2 entry. However, its role in supporting a broad range of SARS-CoV-2 variants, including the emerging Omicron BA.2.86 and JN.1 subvariants, remains to be determined. To address this question, we generated 293- and A549-derived TMEM106B knockout cell lines and assessed their ability to support viral entry for various SARS-CoV-2 variants (D614G, E484D, Omicron BA.1, BA.2, XBB.1.5, BA.2.86, and JN.1) using pseudoviral infection systems. We also examined the role of transmembrane protease serine 2 (TMPRSS2) and other type II transmembrane serine proteases (TTSP) in viral entry and syncytium formation. Our results showed that TMEM106B knockout significantly reduced viral entry across all tested variants. Additionally, overexpression of TMPRSS2, TMPRSS11F and TMPRSS13 in TMEM106B-expressing cells enhanced viral entry and syncytium formation, including BA.2.86 and JN.1 variants. Importantly, we identified two single-nucleotide polymorphisms (SNPs) that result in G2A and N151S variant, respectively, affects TMEM106B receptor function, indicating that selected genetic polymorphisms of TMEM106B gene may impact cell susceptibility to SARS-CoV-2 infection. These findings highlight TMEM106B as a functional receptor for SARS-CoV-2 across different variants, including the latest Omicron subvariants, and provide new insights for the therapeutic interventions targeting viral entry.
跨膜蛋白106B（TMEM106B）已被确定为一种功能性受体，可促进不依赖血管紧张素转换酶2（ACE2）的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）进入细胞。然而，其在支持包括新出现的奥密克戎BA.2.86和JN.1亚变体在内的多种SARS-CoV-2变体方面的作用仍有待确定。为了解决这个问题，我们构建了源自293细胞和A549细胞的TMEM106B基因敲除细胞系，并使用假病毒感染系统评估了它们支持各种SARS-CoV-2变体（D614G、E484D、奥密克戎BA.1、BA.2、XBB.1.5、BA.2.86和JN.1）进入细胞的能力。我们还研究了跨膜蛋白酶丝氨酸2（TMPRSS2）和其他II型跨膜丝氨酸蛋白酶（TTSP）在病毒进入细胞和形成合胞体中的作用。我们的结果表明，TMEM106B基因敲除显著降低了所有测试变体的病毒进入细胞能力。此外，在表达TMEM106B的细胞中过表达TMPRSS2、TMPRSS11F和TMPRSS13可增强病毒进入细胞能力和合胞体形成，包括BA.2.86和JN.1变体。重要的是，我们鉴定出两个分别导致G2A和N151S变体的单核苷酸多态性（SNP），它们影响TMEM106B受体功能，表明TMEM106B基因的特定遗传多态性可能影响细胞对SARS-CoV-2感染的易感性。这些发现突出了TMEM106B作为包括最新奥密克戎亚变体在内的不同SARS-CoV-2变体的功能性受体，并为针对病毒进入的治疗干预提供了新的见解。
