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J Virol. 2018 Jan 30;92(4). pii: e00914-17. doi: 10.1128/JVI.00914-17. Print 2018 Feb 15.

Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus.

Author information

1
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China liangqiming@shsmu.edu.cn jaeujung@med.usc.edu.
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
3
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA liangqiming@shsmu.edu.cn jaeujung@med.usc.edu.
#
Contributed equally

Abstract

The viral Bcl-2 homolog (vBcl2) of Kaposi's sarcoma-associated herpesvirus (KSHV) displays efficient antiapoptotic and antiautophagic activity through its central BH3 domain, which functions to prolong the life span of virus-infected cells and ultimately enhances virus replication and latency. Independent of its antiapoptotic and antiautophagic activity, vBcl2 also plays an essential role in KSHV lytic replication through its amino-terminal amino acids (aa) 11 to 20. Here, we report a novel molecular mechanism of vBcl2-mediated regulation of KSHV lytic replication. vBcl2 specifically bound the tegument protein open reading frame 55 (ORF55) through its amino-terminal aa 11 to 20, allowing their association with virions. Consequently, the vBcl2 peptide derived from vBcl2 aa 11 to 20 effectively disrupted the interaction between vBcl2 and ORF55, inhibiting the incorporation of the ORF55 tegument protein into virions. This study provides new insight into vBcl2's function in KSHV virion assembly that is separable from its inhibitory role in host apoptosis and autophagy.IMPORTANCE KSHV, an important human pathogen accounting for a large percentage of virally caused cancers worldwide, has evolved a variety of stratagems for evading host immune responses to establish lifelong persistent infection. Upon viral infection, infected cells can go through programmed cell death, including apoptosis and autophagy, which plays an effective role in antiviral responses. To counter the host response, KSHV vBcl2 efficiently blocks apoptosis and autophagy to persist for the life span of virus-infected cells. Besides its anti-programmed-cell-death activity, vBcl2 also interacts with the ORF55 tegument protein for virion assembly in infected cells. Interestingly, the vBcl2 peptide disrupts the vBcl2-ORF55 interaction and effectively inhibits KSHV virion assembly. This study indicates that KSHV vBcl2 harbors at least three genetically separable functions to modulate both host cell death signaling and virion production and that the vBcl2 peptide can be developed as an anti-KSHV therapeutic application.

KEYWORDS:

KSHV; Kaposi's sarcoma-associated herpesvirus; ORF55 tegument; autophagy; lytic replication; vBcl2; virion assembly

PMID:
29167347
PMCID:
PMC5790944
DOI:
10.1128/JVI.00914-17
[Indexed for MEDLINE]
Free PMC Article

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