STING facilitates nuclear import of herpesvirus genome during infection

Abstract

Once inside the host cell, DNA viruses must overcome the physical barrier posed by the nuclear envelope to establish a successful infection. The mechanism underlying this process remains unclear. Here, we show that the herpesvirus exploits the immune adaptor stimulator of interferon genes (STING) to facilitate nuclear import of the viral genome. Following the entry of the viral capsid into the cell, STING binds the viral capsid, mediates capsid docking to the nuclear pore complex via physical interaction, and subsequently enables accumulation of the viral genome in the nucleus. Silencing STING in human cytomegalovirus (HCMV)-susceptible cells inhibited nuclear import of the viral genome and reduced the ensuing viral gene expression. Overexpressing STING increased the host cell’s susceptibility to HCMV and herpes simplex virus 1 by improving the nuclear delivery of viral DNA at the early stage of infection. These observations suggest that the proviral activity of STING is conserved and exploited by the herpesvirus family. Intriguingly, in monocytes, which act as latent reservoirs of HCMV, STING deficiency negatively regulated the establishment of HCMV latency and reactivation. Our findings identify STING as a proviral host factor regulating latency and reactivation of herpesviruses.

New feature extraction from phylogenetic profiles improved the performance of pathogen-host interactions

“…The diseases associated with TTN include myopathy and Salih myopathy. The SYNE1 mediates the docking of the capsid protein of human herpesviruses to nuclear pore complex proteins ( Hong et al., 2021 ).…”

Crosstalk between RNA viruses and DNA sensors: Role of the cGAS‐STING signalling pathway

“…[51][52][53] Furthermore, Herpesviridae have evolved to exploit STING for pro-viral functions as HSV-1 and human cytomegalovirus (HCMV) were recently reported to utilise STING for nuclear entry upon binding of viral capsid with STING. 54 In addition to infected cells, the cGAS-STING antiviral innate immune response can spread to neighbouring bystander cells through the release of cGAMP, which amplifies and broadens the host antiviral immunity. Several routes, including the connexinassociated gap junction, 55 the leucine-rich repeat-containing 8 (LRRC8) comprising volume-regulated anion channel (VRAC), [56][57][58] the folate-organic phosphate antiporter solute carrier family 19 member 1 (SLC19A1), 59,60 ATP-gated P2X7 receptor (P2X7R), 61 package of cGAMP into enveloped virions, 62,63 have been reported to mediate the transfer of cGAMP between cells, which confers antiviral responses of the surrounding cells.…”

STING1 in Different Organelles: Location Dictates Function

“…Thus, it is not surprising that STING1 localizes on outer and inner nuclear membranes. STING1 can also co-localize with spectrin repeat containing nuclear envelope protein 1 (SYNE1) at the nuclear lamina, and mediates the docking of capsid protein of human herpes viruses to nuclear pore complex proteins ( 91 ) ( Figure 2 ). These findings provide a framework to explain the import of viral genomes into the nucleus of susceptible cells in the early stages of infection ( 91 ).…”

“…STING1 can also co-localize with spectrin repeat containing nuclear envelope protein 1 (SYNE1) at the nuclear lamina, and mediates the docking of capsid protein of human herpes viruses to nuclear pore complex proteins ( 91 ) ( Figure 2 ). These findings provide a framework to explain the import of viral genomes into the nucleus of susceptible cells in the early stages of infection ( 91 ). Additional studies are required to fully elucidate the mechanism of ER-located STING1 trafficking into the nucleus and other nuclear functions of STING1, particularly in regulating genome transcription and chromosome stabilization.…”