HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway.
Many enveloped viruses exploit the class E vacuolar protein-sorting (VPS) pathway to bud from cells, and use peptide motifs to recruit specific class E VPS factors. Homologous to E6AP COOH terminus (HECT) ubiquitin ligases have been implicated as cofactors for PPXY motif-dependent budding, but precisely which members of this family are responsible, and how they access the VPS pathway is unclear. Here, we show that PPXY-dependent viral budding is unusually sensitive to inhibitory fragments derived from specific HECT ubiquitin ligases, namely WWP1 and WWP2. We also show that WWP1, WWP2, or Itch ubiquitin ligase recruitment promotes PPXY-dependent virion release, and that this function requires that the HECT ubiquitin ligase domain be catalytically active. Finally, we show that several mammalian HECT ubiquitin ligases, including WWP1, WWP2, and Itch are recruited to class E compartments induced by dominant negative forms of the class E VPS ATPase, VPS4. These data indicate that specific HECT ubiquitin ligases can link PPXY motifs to the VPS pathway to induce viral budding.
Martin-Serrano
Juan
J
Aaron Diamond AIDS Research Center and The Rockefeller University, New York, NY 10021, USA.
Eastman
Scott W
SW
Chung
Wayne
W
Bieniasz
Paul D
PD
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D020816:Amino Acid Motifs; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases; D014617:Vacuoles / Q000378:metabolism*; D033921:Vesicular Transport Proteins; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000378:metabolism; D014779:Virus Replication
D056827:Endosomal Sorting Complexes Required for Transport; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C080981:VP40 protein, virus; D033921:Vesicular Transport Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; C471642:WWP1 protein, human; C465283:WWP2 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; D025262:Vacuolar Proton-Translocating ATPases; D000074183:ATPases Associated with Diverse Cellular Activities; C490305:VPS4A protein, human