Herpes simplex virus 1 E3 ubiquitin ligase ICP0 protein inhibits tumor necrosis factor alpha-induced NF-κB activation by interacting with p65/RelA and p50/NF-κB1.
NF-κB plays central roles in regulation of diverse biological processes, including innate and adaptive immunity and inflammation. HSV-1 is the archetypal member of the alphaherpesviruses, 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 ICP0 protein, a viral E3 ubiquitin ligase, was shown to significantly suppress tumor necrosis factor alpha (TNF-α)-mediated NF-κB activation. ICP0 was demonstrated to bind to the NF-κB subunits p65 and p50 by coimmunoprecipitation analysis. ICP0 bound to the Rel homology domain (RHD) of p65. Fluorescence microscopy demonstrated that ICP0 abolished nuclear translocation of p65 upon TNF-α stimulation. Also, ICP0 degraded p50 via its E3 ubiquitin ligase activity. The RING finger (RF) domain mutant ICP0 (ICP0-RF) lost its ability to inhibit TNF-α-mediated NF-κB activation and p65 nuclear translocation and degrade p50. Notably, the RF domain of ICP0 was sufficient to interact with p50 and abolish NF-κB reporter gene activity. Here, it is for the first time shown that HSV-1 ICP0 interacts with p65 and p50, degrades p50 through the ubiquitin-proteasome pathway, and prevents NF-κB-dependent gene expression, which may contribute to immune evasion and pathogenesis of HSV-1.
Soochow University, Institutes of Biology and Medical Sciences, Jiangsu Suzhou, China.
Jie
J
Zhang
Kezhen
K
Wang
Shuai
S
Wang
Chunfu
C
Zheng
D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D017874:Immediate-Early Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1