Yu Tian-Mei, Li Ze-Min, Zhang Wen-Kang, Li Bang, Liu Qiao, Zhou Chuan-Min, Yu Xue-Jie
State Key Laboratory of Virology, School of Public Health, Wuhan University, Wuhan, China.
Gastrointestinal Disease Diagnosis and Treatment Center, The First Hospital of Hebei Medical University, Shijiazhuang, China.
PLoS Pathog. 2025 Jun 3;21(6):e1013201. doi: 10.1371/journal.ppat.1013201. eCollection 2025 Jun.
Severe fever with thrombocytopenia syndrome virus (SFTSV), a tick-borne bunyavirus, causes an emerging viral hemorrhagic fever with a high mortality rate. SFTSV nonstructural protein S (NSs) is a virulence factor that sequesters antiviral proteins into autophagic vesicles for degradation to escape host immune response. SAFA (Nuclear scaffold attachment factor A), an RNA sensor, recognizes viral RNA and is retained in the cytoplasm upon RNA virus SFTSV infection and then activates innate immunity. It is unclear whether NSs mediates the escape of SAFA-mediated antiviral response. Here we showed that SFTSV NSs can inhibit SAFA-dependent antiviral response via autophagy. We used SAFA-NLS (the nuclear localization signal) mutant to transfect SAFA knocked-out MEF cells and found that the cytoplasmic SAFA promoted innate immune response to poly(I:C) stimulating. Importantly, NSs interacted with the AAA+ domain of SAFA and retained SAFA in the cytoplasm thereby suppressing SAFA-mediated antiviral response. Mechanistically, SFTSV NSs degraded cytoplasmic SAFA via SQSTM1/p62-dependent autophagy and sequestered SAFA into autophagic vesicles for degradation through promoting the interaction between SAFA and LC3. In conclusion, our results indicate a novel mechanism of SFTSV NSs to escape host antiviral immune response by recruiting SAFA into autophagic flux for degradation.
严重发热伴血小板减少综合征病毒（SFTSV）是一种蜱传布尼亚病毒，可引发一种具有高死亡率的新型病毒性出血热。SFTSV非结构蛋白S（NSs）是一种毒力因子，它将抗病毒蛋白隔离到自噬小泡中进行降解，以逃避宿主免疫反应。SAFA（核支架附着因子A）作为一种RNA传感器，可识别病毒RNA，在RNA病毒SFTSV感染后被保留在细胞质中，进而激活先天免疫。目前尚不清楚NSs是否介导了SAFA介导的抗病毒反应的逃逸。在此我们表明，SFTSV NSs可通过自噬抑制SAFA依赖的抗病毒反应。我们使用SAFA-NLS（核定位信号）突变体转染SAFA敲除的MEF细胞，发现细胞质中的SAFA促进了对聚肌胞苷酸（poly(I:C)）刺激的先天免疫反应。重要的是，NSs与SAFA的AAA+结构域相互作用，并将SAFA保留在细胞质中，从而抑制SAFA介导的抗病毒反应。从机制上讲，SFTSV NSs通过SQSTM1/p62依赖的自噬降解细胞质中的SAFA，并通过促进SAFA与LC3之间的相互作用将SAFA隔离到自噬小泡中进行降解。总之，我们的结果表明了SFTSV NSs通过将SAFA招募到自噬流中进行降解来逃避宿主抗病毒免疫反应的新机制。
