Herpes Simplex Virus 1 Protein Kinase US3 Hyperphosphorylates p65/RelA and Dampens NF-κB Activation

Abstract

Nuclear factor B (NF-B) plays important roles in innate immune responses by regulating the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation, and survival. To survive in the host cells, viruses have evolved multiple strategies to evade and subvert the host immune response. Herpes simplex virus 1 (HSV-1) bears a large DNA genome, with the capacity to encode many different viral proteins to counteract the host immune responses. In the present study, we demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-B activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 was also shown to hyperphosphorylate p65 at serine 75 and block its nuclear translocation. Two US3 mutants, K220M and D305A, still interacted with p65; however, they could not hyperphosphorylate p65, indicating that the kinase activity of US3 was indispensable for the function. The attenuation of NF-B activation by HSV-1 US3 protein kinase may represent a critical adaptation to enable virus persistence within the host. IMPORTANCEThis study demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-B activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 hyperphosphorylated p65 at serine 75 to inhibit NF-B activation. The kinase activity of US3 was indispensable for its hyperphosphorylation of p65 and abrogation of the nuclear translocation of p65. The present study elaborated a novel mechanism of HSV-1 US3 to evade the host innate immunity.

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

“…It is worth noting that R2621 infection could also counteract cGAS/ STING-mediated activation of IFN pathway, although to a lesser extent than that of WT HSV-1. This observation is consistent with our screening result; for example, US3, VP16, and UL42, which have previously been proved to inhibit IFN production and NF-B activation by targeting IRF3 or p65 (32)(33)(34)(35), could also inhibit cGAS/STING-mediated IFN-␤ activation. Given the fact that IRF3 and p65 are both crucial downstream factors in the cGAS/STING-mediated DNA-sensing signal pathway, it is plausible that US3, VP16, and UL42 inhibit cytosolic DNA-sensing signal in a similar manner.…”

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

“…Both US3 and UL42 interact with p65-RELA to reduce NF-␤ activation (68,69). Further, VP16, the major subnetwork hub, is able to prevent beta inter- …”

Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

“…ICP0, an E3 ubiquitin ligase, disrupts NF-B activation by abrogating p65 nuclear translocation and promoting p50 to proteasomal degradation (35). US3 hyperphosphorylates p65 to inhibit NF-B activation and inflammatory chemokine expression (36). ICP27 inhibits NF-B signaling by stabilizing IB␣ (37).…”