Small non-coding RNAs encoded within the herpes simplex virus type 1 latency associated transcript (LAT) cooperate with the retinoic acid inducible gene I (RIG-I) to induce beta-interferon promoter activity and promote cell survival

Abstract

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is abundantly expressed in latently infected trigeminal ganglionic sensory neurons. Expression of the first 1.5 kb of LAT coding sequences restores wild type reactivation to a LAT null HSV-1 mutant. The anti-apoptosis functions of the first 1.5 kb of LAT coding sequences are important for wild type levels of reactivation from latency. Two small non-coding RNAs (sncRNAs) contained within the first 1.5 kb of LAT coding sequences are expressed in trigeminal ganglia of latently infected mice, they cooperate to inhibit apoptosis, and reduce the efficiency of productive infection. In this study, we demonstrated that LAT sncRNA1 cooperates with the RNA sensor, retinoic acid inducible gene I (RIG-I), to stimulate IFN-β promoter activity and NF-κB dependent transcription in human or mouse cells. LAT sncRNA2 stimulated RIG-I induction of NF-κB dependent transcription in mouse neuroblastoma cells (Neuro-2A) but not human 293 cells. Since it is well established that NF-κB interferes with apoptosis, we tested whether the sncRNAs cooperated with RIG-I to inhibit apoptosis. In Neuro-2A cells, both sncRNAs cooperated with RIG-I to inhibit cold-shock induced apoptosis. Double stranded RNA (PolyI:C) stimulates RIG-I dependent signaling; but enhanced cold-shock induced apoptosis. PolyI:C, but not LAT sncRNAs, interfered with protein synthesis when cotransfected with RIG-I, which correlated with increased levels of cold-shock induced apoptosis. LAT sncRNA1 appeared to interact with RIG-I in transiently transfected cells suggesting this interaction stimulates RIG-I.

A Viral Deamidase Targets the Helicase Domain of RIG-I to Block RNA-Induced Activation

“…Although previous studies implicated RIG-I in sensing dsRNA produced by herpesviruses (da Silva and Jones, 2013; Jacquemont and Roizman, 1975; Rasmussen et al, 2009; Weber et al, 2006), our work provides further credence concerning the RIG-I-mediated immune defense against a model DNA virus and viral immune evasion thereof. HSV-1 infection prevents RIG-I activation and innate immune responses triggered by subsequent SeV infection.…”

The Latency-Associated Transcript Inhibits Apoptosis via Downregulation of Components of the Type I Interferon Pathway during Latent Herpes Simplex Virus 1 Ocular Infection

“…Despite some early skepticism, the ability of the HSV-1 LAT to inhibit apoptosis has been well documented in various infection models and is now widely accepted (13)(14)(15)(16)(17)(18)(19). Furthermore, antiapoptotic activity of LAT likely plays a role in controlling the latency reactivation cycle.…”

“…Additionally, two small noncoding RNAs (sncRNAs) within the 2-kb LAT which are not present in the LAT Ϫ virus have been described (64). These sncRNAs have been implicated in protection from apoptosis (19) and affect upregulation of HVEM (herpesvirus entry mediator) and, thus, increase in reactivation from latency (65). Whether these two sncRNAs mediate this LAT-dependent inhibition of JAK-1 and JAK-2 is under investigation.…”

Suppression of PACT-Induced Type I Interferon Production by Herpes Simplex Virus 1 Us11 Protein

“…RIG-I-like receptors are critically involved in the sensing of HSV infection (20,21). Particularly, HSV-1-encoded small noncoding RNAs derived from the latency-associated transcript are sensed by RIG-I (22). Optimal function of RIG-I requires PACT, which interacts with and potently activates RIG-I in a PKR-independent manner (23).…”