Herpes simplex virus 1 (HSV-1) is the archetypal member of the alphaherpesvirus 
with a large genome encoding over 80 viral proteins, many of which are involved 
in virus-host interactions and show immune modulatory capabilities. In this 
study, we demonstrated that the HSV-1 UL42 protein, a DNA polymerase 
processivity factor, was a novel antagonism of the canonical NF-κB signaling 
pathway. UL42 was shown to significantly suppress TNF-α mediated NF-κB 
activation. Co-immunoprecipitation experiment revealed that UL42 bound to the 
NF-κB subunits p65 and p50. Fluorescence microscopy demonstrated that UL42 
abolished nuclear translocation of p65 and p50 upon TNF-α-stimulation. But the 
inhibiting capacity of UL42 2R/2A (R279A, R280A) and UL42 3R/3A (R113A, R279A 
and R280A) mutants were less than wild type UL42. Also UL42 bound to the Rel 
homology domain of the NF-κB subunit p65 and p50. Notably, the N-terminal of 
UL42 was sufficient to interact with p65 and p50 and abolished NF-κB reporter 
gene activity. Thus, it was first time we demonstrated that HSV-1 UL42 appeared 
to prevent NF-κB-dependent gene expression by retaining p65 and p50 in the 
cytoplasm, and UL42-dependent transcriptional activation were inherently coupled 
to promote HSV-1 lytic replication, which also may contribute to immune evasion 
and pathogenesis of HSV-1.