A Study On Mechanism Of NEAT1 And SRSF2 Regulating HSV-1 Replication

Herpes Simplex Virus type 1(HSV-1)infection often result in herpes and encephalitis of orofacial and genital,even encephalitis.Like other viruses,HSV-1 exploits a series of cellular protein factors to facilitate the progression of its life cycle.This study focuses on the roles and mechanism of long non-coding RNA(lncRNA)NEAT1,transcriptional factor STAT3,splicing factor SRSF2 and nuclear body paraspeckle and speckle in regulating HSV-1 replication.Paraspeckles are subcellular structure found in the nuclei of mammalian cells and are formed by lncRNA NEAT1 and numerous RNA-binding proteins.NEAT1 is an essential architectural component of paraspeckles.In addition to NEAT1,paraspeckles also contain core protein components,including PSPC1,P54 nrb.The expression of NEAT1 gene has been shown to be upregulated during infection by HSV-1.However,the importance of the alteration of NEAT1 expression level in HSV-1 genes expression and replication is currently unclear.Here,we investigated the role of NEAT1 and paraspeckles in HSV-1 replication and viral gene expression and found that HSV-1 infection upregulates NEAT1 expression and paraspeckle formation in a STAT3-dependent manner.NEAT1 and other paraspeckle components can bind to the viral genes and help them retain in paraspeckles.PSPC1,a component of paraspeckles,is required for the recruitment of STAT3 to paraspeckles and facilitates the interaction between viral genes and STAT3,finally increasing viral gene expression and viral replication.Furthermore,thermosensitive gel containing NEAT1 siRNA or STAT3 siRNA effectively healed the skin lesions caused by HSV-1 infection in mice.SRSF2 is a specific well-known component of subcellular structure speckle and functions as a mediator of genome stability,pre-mRNA splicing,mRNA nuclear export and translational control.To date,several studies have investigated the roles of SRSF2 in HIV-1 and HPV16 viral infection.However,the effects of SRSF2 on the HSV-1 infection process have not been elucidated.In this report,we reveal that the host splicing factor SRSF2 facilitates HSV-1 replication by regulating HSV-1 ICP0,ICP27 and TK expressional level.At the transcriptional level,SRSF2 functions as a transcriptional activator by directly binding to the HSV-1 ICP0,ICP27 and TK promoters.At the post-transcriptional level,SRSF2 participates in ICP0 pre-mRNA splicing by co-localizing with ICP0 exon 3.Taken together,we demonstrate HSV-1 can use lncRNA NEAT1,transcriptional factor STAT3,splicing factor SRSF2 and nuclear body paraspeckle and speckle of host cells to facilitate viral genes expression and enhance viral replication.The components of these structures are expected to be potential therapeutic targets to treatment HSV-1 infection related diseases.