E3 ligase RNF5 inhibits type I interferon response in herpes simplex virus keratitis through the STING/IRF3 signaling pathway

Abstract

Herpes simplex keratitis (HSK), caused by the herpes simplex virus 1 (HSV-1), is a major blinding disease in developed countries. HSV-1 can remain latent in the host for life and cannot be eradicated. The infection causes the secretion of various cytokines and aggregation of inflammatory cells. In the early stage of inflammation, mainly neutrophils infiltrate the cornea, and CD4+ T cells mediate the immunopathological changes in herpetic stromal keratitis in the subsequent progression. The STING/IRF3-mediated type I interferon (IFN) response can effectively inhibit viral replication and control infection, but the activity of STING is affected by various ubiquitination modifications. In this study, we found that the expression of RNF5 was elevated in corneal tissues and corneal epithelial cells after infection with HSV-1. Immunofluorescence staining confirmed that RNF5 was mainly expressed in the corneal epithelial layer. We silenced and overexpressed RNF5 expression in corneal epithelial cells and then inoculated them with HSV-1. We found that the expressions of STING, p-IRF3, p-TBK1, and IFN-β mRNA increased after RNF5 silencing. The opposite results were obtained after RNF5 overexpression. We also used siRNA to silence RNF5 in the mouse cornea and then established the HSK model. Compared with the siRNA-control group, the siRNA-RNF5 group showed significantly improved corneal inflammation, reduced clinical scores and tear virus titers, and significantly increased corneal IFN-β expression. In addition, the expressions of the proinflammatory cytokines IL-6 and TNF-α in the corneal tissue were significantly decreased, indicating that RNF5 silencing could effectively promote IFN-I expression, inhibit virus replication, alleviate inflammation, and reduce corneal inflammatory damage. In summary, our results suggest that RNF5 limits the type I IFN antiviral response in HSV corneal epithelitis by inhibiting STING/IRF3 signaling.

A transcriptome-wide Mendelian randomization study in isolated human immune cells highlights risk genes involved in viral infections and potential drug repurposing opportunities for schizophrenia

“…Intriguingly, ZNF823 and MAPK3 both belong to the HSV-1 infection (hsa05168) KEGG pathway, while MAPK3 was also found to be up-regulated in placentas from pregnancies with SARS-CoV-2 (COVID-19) maternal infection 23 . Furthermore, RNF5 has been shown to inhibit type I interferon responses in HSV keratitis through the cGAS-STING/IRF3 signalling pathway 64 . Taken together, this is strong evidence consistent with a role for IRF3 in coordinating the expression of a sub-network of putative SCZ risk genes, many of which are already known to be involved in modulating responses to viral infections.…”

Herpes simplex keratitis: A brief clinical overview

“…The HSV causes HSK[ 24 ], It is among the most ubiquitous human pathogens on earth[ 25 - 27 ]; and a major blinding disease in developed countries[ 28 , 29 ]. It is the second most common cause of corneal scarring according to a large study[ 30 ], It has a seroprevalence in the range of 60%-90%[ 31 ].…”

RNF5: inhibiting antiviral immunity and shaping virus life cycle

“…HSV-1 infection often results in corneal opacity and haze, with numerous neutrophils infiltrated the cornea, eventually leading to blindness due to inflammation and angiogenesis (37). RNF5 was shown to be constitutively expressed in corneal tissues and its expression increased upon HSV-1 infection, leading to a decrease in STING content through ubiquitination and degradation (31). Silencing RNF5 inhibited viral replication and reduced the number of inflammatory cells and the secretion of proinflammatory cytokines, thus alleviating corneal tissue injury.…”

“…Notably, the PRV envelope protein UL13, a novel viral immunoevasion protein, can collaborate with RNF5 to induce ubiquitination and degradation of STING, thereby inhibiting the antiviral immune response (30). Moreover, during infection with herpes simplex virus type 1 (HSV-1), RNF5 expression is upregulated in corneal tissues and corneal epithelial cells (31). This increase leads to a significant reduction in STING levels through ubiquitination and degradation.…”