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Long Noncoding RNA NRAV Promotes Respiratory Syncytial Virus Replication by Targeting the MicroRNA miR-509-3p/Rab5c Axis To Regulate Vesicle Transportation.
Journal of Virology ( IF 5.4 ) Pub Date : 2020-05-04 , DOI: 10.1128/jvi.00113-20
Jian Li 1, 2, 3 , Miao Li 1, 2 , Xiuli Wang 1, 2, 4 , Mengfei Sun 1, 2 , Cuiqing Ma 1, 2 , Wenzhang Liang 1, 2, 3 , Xue Gao 1, 2 , Lin Wei 2, 5
Affiliation  

Respiratory syncytial virus (RSV) is an enveloped RNA virus which is responsible for approximately 80% of lower respiratory tract infections in children. Current lines of evidence have supported the functional involvement of long noncoding RNA (lncRNA) in many viral infectious diseases. However, the overall biological effect and clinical role of lncRNAs in RSV infection remain unclear. In this study, lncRNAs related to respiratory virus infection were obtained from the lncRNA database, and we collected 144 clinical sputum specimens to identify lncRNAs related to RSV infection. Quantitative PCR (qPCR) detection indicated that the expression of lncRNA negative regulator of antiviral response (NRAV) in RSV-positive patients was significantly lower than that in uninfected patients, but lncRNA psoriasis-associated non-protein coding RNA induced by stress (PRINS), nuclear paraspeckle assembly transcript 1 (NEAT1), and Nettoie Salmonella pas Theiler's (NeST) showed no difference in vivo and in vitro Meanwhile, overexpression of NRAV promoted RSV proliferation in A549 and BEAS-2B cells, and vice versa, indicating that the downregulation of NRAV was part of the host antiviral defense. RNA fluorescent in situ hybridization (FISH) confirmed that NRAV was mainly located in the cytoplasm. Through RNA sequencing, we found that Rab5c, which is a vesicle transporting protein, showed the same change trend as NRAV. Subsequent investigation revealed that NRAV was able to favor RSV production indirectly by sponging microRNA miR-509-3p so as to release Rab5c and facilitate vesicle transportation. The study provides a new insight into virus-host interaction through noncoding RNA, which may contribute to exploring potential antivirus targets for respiratory virus.IMPORTANCE The mechanism of interaction between RSV and host noncoding RNAs is not fully understood. In this study, we found that the expression of long noncoding RNA (lncRNA) negative regulator of antiviral response (NRAV) was reduced in RSV-infected patients, and overexpression of NRAV facilitated RSV production in vitro, suggesting that the reduction of NRAV in RSV infection was part of the host antiviral response. We also found that NRAV competed with vesicle protein Rab5c for microRNA miR509-3p in cytoplasm to promote RSV vesicle transport and accelerate RSV proliferation, thereby improving our understanding of the pathogenic mechanism of RSV infection.

中文翻译:

长非编码RNA NRAV通过靶向MicroRNA miR-509-3p / Rab5c轴来调节囊泡运输,从而促进呼吸道合胞病毒复制。

呼吸道合胞病毒(RSV)是一种包膜RNA病毒,约占儿童下呼吸道感染的80%。当前的证据支持长非编码RNA(lncRNA)在许多病毒感染性疾病中的功能性参与。但是,尚不清楚lncRNA在RSV感染中的总体生物学效应和临床作用。在这项研究中,从lncRNA数据库获得了与呼吸道病毒感染相关的lncRNA,我们收集了144份临床痰标本,以鉴定与RSV感染相关的lncRNA。定量PCR(qPCR)检测表明,RSV阳性患者中lncRNA抗病毒反应负调节剂(NRAV)的表达明显低于未感染患者,但是,lncRNA牛皮癣相关的非蛋白编码RNA可以通过压力(PRINS),核副斑点装配转录本1(NEAT1)和Nettoie Salmonella pas Theiler(NeST)诱导,在体内和体外均无差异。同时,NRAV的过表达促进RSV增殖在A549和BEAS-2B细胞中的表达反之亦然,这表明NRAV的下调是宿主抗病毒防御的一部分。RNA荧光原位杂交(FISH)证实NRAV主要位于细胞质中。通过RNA测序,我们发现Rab5c是一种囊泡转运蛋白,其变化趋势与NRAV相同。随后的研究表明,NRAV通过海绵化microRNA miR-509-3p从而间接释放RSV,从而释放Rab5c并促进囊泡运输。该研究为通过非编码RNA进行的病毒-宿主相互作用提供了新的见解,这可能有助于探索呼吸道病毒的潜在抗病毒靶标。重要信息尚未完全了解RSV与宿主非编码RNA之间的相互作用机理。在这项研究中,我们发现在RSV感染的患者中,抗病毒应答(NRAV)的长非编码RNA(lncRNA)负调节剂的表达降低了,并且NRAV的过表达促进了体外RSV的产生,这表明RSV中NRAV的降低感染是宿主抗病毒反应的一部分。我们还发现,NRAV与囊泡蛋白Rab5c竞争细胞质中的microRNA miR509-3p,以促进RSV囊泡转运并加速RSV增殖,从而增进了我们对RSV感染的致病机制的了解。
更新日期:2020-05-04
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