TRIM21 Aggravates Herpes Simplex Virus Epithelial Keratitis by Attenuating STING-IRF3-Mediated Type I Interferon Signaling

Abstract

Herpes simplex virus-1 (HSV-1) is the leading cause of infectious blindness in the developed world. HSV-1 infection can occur anywhere in the eye, and the most common presentation is epithelial keratitis. In the HSV epithelial keratitis mice model, we detected the expression of TRIM21 and then investigated the clinical relationship between TRIM21 and HSV epithelial keratitis by silencing TRIM21. Through the clinical scores and histopathology examination, we found that TRIM21 can effectively reduce the severity of HSV epithelial keratitis. Furthermore, silencing TRIM21 significantly controlled the virus particle release at 1, 3, and 5 days post-HSV-1 infection. Notably, the production of IFNβ was enhanced, and the secretion of pro-inflammatory cytokines (IL-6 and TNF-a) was inhibited. Next, human corneal epithelial cells were pretreated with lentivirus or siRNA, respectively, so that TRIM21 expression was overexpressed or silenced. We focused on the regulation of STING-IRF3 and type I interferon signaling after infected with HSV-1. In conclusion, our results have identified that TRIM21 is abnormally high expressed in HSV epithelial keratitis. TRIM21 enhances the replication of HSV-1 in corneal epithelial cells via suppressing the production of type I IFN by inhibiting STING/IRF3 signaling. It also promotes the secretion of IL-6 and TNF-a, thereby aggravating the severity of HSV epithelial keratitis.

PARP‐1 involves in UVB‐induced inflammatory response in keratinocytes and skin injury via regulation of ROS‐dependent EGFR transactivation and p38 signaling

“…Alternatively, UV irradiation can induce a variety of pro‐inflammatory cytokines via infiltrated immune cells which coordinate to control skin homeostasis. For example, UVB‐induced NF‐κB activation via STING leads to the production of type I IFN from inflammatory monocytes, 61 and confers a protective function to decrease pro‐inflammatory genes and inflammation response in the skin 61,62 . Taken together, it still needs to decipher the detailed cellular events of PARP‐1 in UV‐stressed skin tissues that can be the direct actions in dermal immune cells and the intricate cellular cross talk in the stressed microenvironment between keratinocytes and immune cells.…”

Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

“… Liu et al (2018) reported that ZIKV-induced NF-κB activation promoted the expression of Drosophila STING and triggered autophagy to clear the virus. It is noteworthy that during HSV-1 infection, autophagy activation rather than type I IFN signaling seems to be the main effector function of STING in regulating viral infection ( Tan and Xia, 2020 ; Yamashiro et al, 2020 ). A similar function of STING-dependent autophagy was also found in infections with pathogenic bacteria such as M. tuberculosis , Listeria innocua , and Staphylococcus aureus ( Watson et al, 2012 ; Moretti et al, 2017 ).…”

African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3

“…The tripartite motif protein 21 (TRIM21) plays a regulatory role in innate immune responses by interacting with antiviral factors. Studies have shown that TRIM21 has a wide range of regulatory effects on IRF3-mediated type I IFN ( Stacey et al., 2012 ; Tan and Xia, 2020 ). To verify interaction between MGF360-14L and TRIM21, HEK293T cells and PK15 were co-transfected with MGF360-14L-Flag and TRIM21-HA plasmids, respectively.…”