Recombinant Epstein-Barr virus Deneddylase BPLF1 (BPLF1), partial

Function

Large tegument protein that plays multiple roles in the viral cycle. During viral entry, remains associated with the capsid while most of the tegument is detached and participates in the capsid transport toward the host nucleus. Plays a role in the routing of the capsid at the nuclear pore complex and subsequent uncoating. Within the host nucleus, acts as a deneddylase and promotes the degradation of nuclear CRLs (cullin-RING ubiquitin ligases) and thereby stabilizes nuclear CRL substrates, while cytoplasmic CRLs remain unaffected. These modifications prevent host cell cycle S-phase progression and create a favorable environment allowing efficient viral genome replication. Participates later in the secondary envelopment of capsids. Indeed, plays a linker role for the association of the outer viral tegument to the capsids together with the inner tegument protein (By similarity). Counteracts host TLR-mediated NF-kappa-B activation through both MYD88 and TICAM1-dependent pathways by interfering with 'Lys-63'- and 'Lys-48'-linked ubiquitination of signaling intermediates such as TRAF6 and IKBKG (PubMed:24586164). Inhibits type I interferon production by forming a tri-molecular complex with host TRIM25 and 14-3-3 thereby promoting TRIM25 autoubiquitination and sequestration of the ligase into inactive protein aggregates (PubMed:31710640). In turn, host RIGI is recruited to the complex but ubiquitination is severely impaired leading to inhibition of the pathway (PubMed:29357390). Also catalyzes the removal of 'Lys-48'- and 'Lys-63'-linked ubiquitin chains on host TBK1 and STING1 suppressing cGAS-STING signaling in addition to the RIGI-MAVS pathway (PubMed:36802409). Inhibits selective autophagy by deubiquitinating host SQSTM1. In turn, decreased SQSTM1 ubiquitination fails to recruit LC3 to SQSTM1-positive aggregates (PubMed:34543352). In the host nucleus, deubiquitinates topoisomerase II subunits TOP2A and TOP2B thereby stabilizing SUMOylated TOP2 which halts the DNA damage response to TOP2-induced double strand DNA breaks and promotes cell survival (PubMed:34543352)

Subcellular Location

Virion tegument; Host cytoplasm; Host nucleus

Subunit

Interacts with host CUL1 and CUL4A; these interactions inhibit the E3 ligase activity of cullins (PubMed:22474075). Interacts with inner tegument protein. Interacts with capsid vertex specific component CVC2. Interacts with the major capsid protein/MCP (By similarity). Interacts with host TRIM25 and YWHAZ (PubMed:29357390, PubMed:31710640)

• Baer R. et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. — Nature (1984)
• de Jesus O. et al. Updated Epstein-Barr virus (EBV) DNA sequence and analysis of a promoter for the BART (CST, BARF0) RNAs of EBV. — Virology (2003)
• Johannsen E. et al. Proteins of purified Epstein-Barr virus. — Proc. Natl. Acad. Sci. U.S.A. (2004)
• Whitehurst C.B. et al. The EBV deubiquitinating enzyme, BPLF1, reduces EBV ribonucleotide reductase activity. — J. Virol. (2009)
• Gastaldello S. et al. A deneddylase encoded by Epstein-Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases. — Nat. Cell Biol. (2010)
• Gastaldello S. et al. Herpes virus deneddylases interrupt the cullin-RING ligase neddylation cycle by inhibiting the binding of CAND1. — J. Mol. Cell Biol. (2012)
• van Gent M. et al. Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling. — PLoS Pathog. (2014)
• Gupta S. et al. Herpesvirus deconjugases inhibit the IFN response by promoting TRIM25 autoubiquitination and functional inactivation of the RIG-I signalosome. — PLoS Pathog. (2018)