Abstract
Nuclear scaffold attachment factor A (SAFA) is a novel RNA sensor involved in sensing viral RNA in the nucleus and mediating antiviral immunity. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a bunyavirus that causes SFTS with a high fatality rate of up to 30%. It remains elusive whether and how cytoplasmic SFTSV can be sensed by the RNA sensor SAFA. Here, we demonstrated that SAFA was able to detect SFTSV infection and mediate antiviral interferon and inflammatory responses. Transcription and expression levels of SAFA were strikingly upregulated under SFTSV infection. SAFA was retained in the cytoplasm by interaction with SFTSV nucleocapsid protein (NP). Importantly, SFTSV genomic RNA was recognized by cytoplasmic SAFA, which recruited and promoted activation of the STING-TBK1 signaling axis against SFTSV infection. Of note, the nuclear localization signal (NLS) domain of SAFA was important for interaction with SFTSV NP and recognition of SFTSV RNA in the cytoplasm. In conclusion, our study reveals a novel antiviral mechanism in which SAFA functions as a novel cytoplasmic RNA sensor that directly recognizes RNA virus SFTSV and mediates an antiviral response.
Highlights
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a severe tick-borne bunyavirus first discovered in China in 2009, and subsequently reported in South Korea, Japan, Vietnam, Pakistan, and Thailand [1,2,3,4,5,6,7]
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an RNA virus with a high fatality rate of up to 30%, which replicates exclusively in the cytoplasm
Under SFTSV infection, scaffold attachment factor A (SAFA) was retained in the cytoplasm and recognized SFTSV infection by interaction with SFTSV nucleocapsid protein (NP) and cytoplasmic SFTSV RNA directly
Summary
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a severe tick-borne bunyavirus first discovered in China in 2009, and subsequently reported in South Korea, Japan, Vietnam, Pakistan, and Thailand [1,2,3,4,5,6,7]. Multiple innate immune escape strategies of SFTSV have been introduced, which are mainly dependent on SFTSV NSs. Previous studies reported that TANK-binding kinase 1 (TBK1), inhibitor of nuclear factor kappa B kinase subunit epsilon (IKKε), retinoic acid-inducible gene I (RIG-I), signal transducer, and activator of transcription 1 and 2 (STAT1 and STAT2), interferon regulatory factor 3 (IRF3), and IRF7 were sequestered by SFTSV NSs into inclusion bodies to suppress antiviral innate immunity [15,16,17,18,19,20,21,22]. SFTSV replication occurs exclusively in the cytoplasm [23], which is detected by cytoplasmic RNA sensors such as RIG-I and melanoma differentiation-associated gene 5 (MDA5) [23,24]. RIG-I and MDA5 recruit mitochondrial antiviral signaling (MAVS) protein, which leads to activation of downstream kinases TBK1/IKKε/IRF3 and induces production of type I IFNs [25]
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