Herpes simplex virus UL56 interacts with and regulates the Nedd4-family ubiquitin ligase Itch.
BACKGROUND
Herpes simplex virus type 2 (HSV-2) is one of many viruses that exploits and modifies the cellular ubiquitin system. HSV-2 expresses the tegument protein UL56 that has been implicated in cytoplasmic transport and/or release of virions, and is a putative regulatory protein of Nedd4 ubiquitin ligase. In order to elucidate the biological function of UL56, this study examined the interaction of UL56 with the Nedd4-family ubiquitin ligase Itch and its role in the regulation of Itch. Additionally, we assessed the similarity between UL56 and regulatory proteins of Itch and Nedd4, Nedd4-family-interactins proteins (Ndfip).


RESULTS
UL56 interacted with Itch, independent of additional viral proteins, and mediated more striking degradation of Itch, compared to Nedd4. Moreover, it was suggested that the lysosome pathway as well as the proteasome pathway was involved in the degradation of Itch. Other HSV-2 proteins with PY motifs, such as VP5 and VP16, did not mediate the degradation of endogenous Itch. Ndfip1 and Ndfip2 were similar in subcellular distribution patterns to UL56 and colocalized with UL56 in co-transfected cells.


CONCLUSIONS
We believe that this is the first report demonstrating the interaction of a HSV-specific protein and Itch. Thus, UL56 could function as a regulatory protein of Itch. The mechanism, function and significance of regulating Itch in HSV-2 infection remain unclear and warrant further investigation.
Ushijima
Yoko
Y
Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Luo
Chenhong
C
Kamakura
Maki
M
Goshima
Fumi
F
Kimura
Hiroshi
H
Nishiyama
Yukihiro
Y
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; C477747:NDFIP2 protein, human; D012097:Repressor Proteins; C546869:UL56 protein, Human herpesvirus 2; D014764:Viral Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex