Abstract
The cellular endosomal sorting complex required for transport (ESCRT) machinery participates in membrane scission and cytoplasmic budding of many RNA viruses. Here, we found that expression of dominant negative ESCRT proteins caused a blockade of Epstein-Barr virus (EBV) release and retention of viral BFRF1 at the nuclear envelope. The ESCRT adaptor protein Alix was redistributed and partially colocalized with BFRF1 at the nuclear rim of virus replicating cells. Following transient transfection, BFRF1 associated with ESCRT proteins, reorganized the nuclear membrane and induced perinuclear vesicle formation. Multiple domains within BFRF1 mediated vesicle formation and Alix recruitment, whereas both Bro and PRR domains of Alix interacted with BFRF1. Inhibition of ESCRT machinery abolished BFRF1-induced vesicle formation, leading to the accumulation of viral DNA and capsid proteins in the nucleus of EBV-replicating cells. Overall, data here suggest that BFRF1 recruits the ESCRT components to modulate nuclear envelope for the nuclear egress of EBV.
Highlights
The endosomal sorting complex required for transport (ESCRT) machinery is conserved evolutionarily and involved in catalyzing the scission of membrane necks in endosome sorting, biogenesis of multivesicular bodies (MVBs), cytokinesis and release of enveloped virions
The cellular endosomal sorting complex required for transport (ESCRT) machinery is known to participate in the biogenesis of multivesicular bodies, cytokinesis and the release of enveloped viruses from cytoplasmic membranes
Specific interactions between BFRF1 and apoptosis linked gene-2 interacting protein X (Alix) are required for BFRF1-derived vesicle formation and crucial for the nuclear egress of Epstein-Barr virus (EBV)
Summary
The endosomal sorting complex required for transport (ESCRT) machinery is conserved evolutionarily and involved in catalyzing the scission of membrane necks in endosome sorting, biogenesis of multivesicular bodies (MVBs), cytokinesis and release of enveloped virions. In addition to the regular composition, cellular ESCRT-I protein TSG101 (tumor susceptibility gene 101) alternatively activates the spiral assembly of ESCRT-III through bridging by the ESCRT associated protein apoptosis linked gene-2 interacting protein X (Alix) [5]. Because these class E proteins are recruited sequentially and assembled for their functions, the interactiondisrupted mutants of Alix and Chmps, as well as the ATPase activity defective Vps (e.g. Vps4AE228Q), are useful tools to investigate the involvement of the ESCRT machinery in various biological processes [6,7,8,9]
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