The Antiviral Apparatus: STING and Oncolytic Virus Restriction

Abstract

A network of pattern recognition receptors (PRRs) is responsible for the detection of invading viruses and acts as the trigger for the host antiviral response. Central to this apparatus is stimulator of interferon genes (STING), which functions as a node and integrator of detection signals. Owing to its role in both intrinsic and adaptive immunity, STING has become a focus for researchers in the field of oncolytic virotherapy. In this review, we consider the function of the cGAS-STING axis and its regulation, both by cellular mechanisms and as a result of viral interference.

Keywords: HSV; IFI16; STING; cGAS; cancer; immunotherapy; interferon; oncolytic virotherapy.

Figure 1

The Antiviral Apparatus Double-stranded DNA from a replicating virus can be bound by cGAS, triggering production of cGAMP—a process that is stimulated by de-SUMOylation of cGAS by SENP7. IFI16 also feeds into this process and participates in cGAS activation and downstream signaling on multiple levels. Signaling through STING begins with cGAMP binding and results in downstream phosphorylation of TBK1 and transcription factors NF-kB and IRF3. NF-kB and IRF3 participate in transcription of type I interferons, interferon-stimulated genes, and inflammatory cytokines. Detection of viral DNA in the nuclear compartment is mediated by IFI16, which triggers signaling on the cGAS/STING axis. RNA polymerase III (pol III) can bind viral DNA and transcribe RNA, thus acting as a DNA pattern recognition receptor. Viral double-stranded RNA can be bound by RIG-I, which in conjunction with MAVS, can activate signaling through STING and TBK1.