Suppression of NF-κB signaling by Pseudorabies virus DNA polymerase processivity factor UL42 via recruiting SOCS1 to promote the ubiquitination degradation of p65

The NF-kappa B pathway is a critical signaling involved in the regulation of the inflammatory and innate immune responses. Previous studies have shown that Pseudorabies Virus (PRV), a porcine alpha herpesvirus, could lead to the phosphorylation and nucleus translocation of p65 while inhibiting the expression of NF-kappa B-dependent inflammatory cytokines, which indicated that there may be unknown mechanisms downstream of p65 that downregulate the activation of NF-kappa B signaling. Here, we found that PRV DNA polymerase factor UL42 inhibited TNF alpha-, LPS-, IKK alpha-, IKK beta-, and p65-mediated transactivation of NF-kappa B signaling, which demonstrated UL42 worked either at or downstream of p65. In addition, it was found that the DNA-binding activity of UL42 was required for inhibition of NF-kappa B signaling. Importantly, it was revealed that UL42 could induce the ubiquitination degradation of p65 by upregulating the suppressor of cytokine signaling 1 (SOCS1). Additionally, it was found that UL42 could promote the K6/K29-linked ubiquitination of p65. Finally, knockdown of SOCS1 attenuated the replication of PRV and led to a significant increase of the inflammatory cytokines. Taken together, our findings uncovered a novel mechanism that PRV-UL42 could upregulated SOCS1 to promote the ubiquitination degradation of p65 to prevent excessive inflammatory response during PRV infection.

Automated summary

This study uncovered a novel mechanism in which PRV-UL42 upregulates SOCS1 to promote the ubiquitination degradation of p65, preventing excessive inflammatory response during PRV infection.