Abstract
Nedd4 is a family of ubiquitin E3 ligases that regulate numerous cellular processes. In this report, we showed that alpha- and beta-herpesviruses have membrane proteins that regulate the function of the Nedd4 family members. Although the homology search score was quite low, UL56 of herpes simplex virus type 1 and 2, ORF0 of varicella-zoster virus, UL42 of human cytomegalovirus, and U24 of human herpesvirus 6A, 6B, and 7 all possess at least one PPxY (PY) motif in their cytoplasmic domain, and are able to bind with Itch, a member of the Nedd4 family. These viral proteins altered the localization of Itch and decreased Itch expression in co-expressing cells. In addition, these viral proteins reduced the production of retrovirus vectors through the regulation of the Nedd4 family of proteins. U24, but not the other proteins, effectively reduced CD3ε expression on the T cell surface. These viral molecules are thought to contribute to the specific function of each virus through the regulation of Nedd4 family activity.
Highlights
Ubiquitination, which is a post-translational modification whereby a highly conserved 76-amino acid polypeptide is attached to a protein, is essential for numerous eukaryotic cellular processes, including protein turnover, protein sorting, cell cycle control, and signal transduction[1]
The amount of FLAG-Itch was markedly reduced in cells when co-expressed with the wild-type viral proteins but not with PY motif-disrupted (PA) mutants or KSHV ORF16 (Fig. 2)
These results suggest that PY motif-containing viral proteins decreased Itch expression
Summary
Ubiquitination, which is a post-translational modification whereby a highly conserved 76-amino acid polypeptide is attached to a protein, is essential for numerous eukaryotic cellular processes, including protein turnover, protein sorting, cell cycle control, and signal transduction[1]. The Nedd[4] (neural precursor cell-expressed developmentally down-regulated gene 4) family of ubiquitin E3 ligases is found in eukaryotes from yeast to mammals. Nedd[4] proteins ubiquitinate their substrate proteins through their interaction with WW domains and PY motifs. A number of Nedd4-interacting proteins (e.g., Ndfip[1] and 2) act as adaptors that regulate Nedd[4] protein catalytic activity[9]. HSV, HCMV, and EBV have Nedd4-binding proteins: UL56, UL42, and LMP2A, respectively. These are membrane proteins that contain a small number of PY motifs that interact with the Nedd[4] family proteins[16,17,18]. We show that these proteins interacted with Itch, and acted as adaptor proteins for the modulation of Nedd[4] protein activity
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