The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency

被引:13
|
作者
Lin, Xiaoxi [1 ]
Sun, Rui [1 ]
Zhang, Fang [1 ]
Gao, Yuan [1 ]
Bin, Lianghua [3 ]
Lan, Ke [2 ]
机构
[1] Chinese Acad Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai, Peoples R China
[2] Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan, Hubei, Peoples R China
[3] Jinan Univ, Biomed Translat Res Inst, Guangzhou, Guangdong, Peoples R China
基金
美国国家卫生研究院;
关键词
KSHV; LANA; ChIP-seq; SENP6; sumoylation; Kaposi's sarcoma-associated herpesvirus; PML ONCOGENIC DOMAINS; DNA-SEQUENCES; CELL-LINE; LYTIC REPLICATION; TERMINAL REPEAT; BINDING-SITES; LANA PROTEIN; TRANSCRIPTION; SUMO; INTERACTS;
D O I
10.1128/JVI.00806-17
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Kaposi's sarcoma-associated herpesvirus (KSHV), which belongs to the Gammaherpesviridae, typically displays two different phases in its life cycle, the latent phase and the lytic phase. Latency-associated nuclear antigen (LANA), the primary viral product during latency, has been reported to bind to a series of cellular gene promoters to modulate gene transcription. To systemically elucidate the cellular genes regulated by LANA, we identified genome-wide LANA binding sites by chromatin immunoprecipitation coupled with sequencing (ChIP-seq). We stratified ChIP-seq data and found that LANA might be involved in the macromolecule catabolic process. Specifically, we found and verified that LANA could directly bind to the promoter of the SUMO/ sentrin-specific peptidase 6 (SENP6) gene in vivo and in vitro. LANA could repress SENP6 promoter activity in a dose-dependent manner in a reporter gene assay. LANA expression was sufficient to inhibit endogenous SENP6 expression at both the RNA and protein levels. Moreover, SENP6 overexpression in KSHV-infected cells reduced LANA at the protein level. Mechanistically, we found that SENP6 could interact with LANA and reduce the formation of sumoylated LANA, which relies on the desumoylation ability of SENP6. During de novo infection, SENP6 overexpression would decrease the abundance of LANA and enhance viral gene expression, which would hamper the establishment of latency. Taken together, these data suggest that KSHV-encoded LANA could inhibit SENP6 expression to regulate the abundance of itself, which may play an important role in controlling the establishment of latency. IMPORTANCE LANA, as a key latent protein produced by KSHV, is responsible for episome persistence and regulates viral reactivation. In the present study, our results demonstrated that LANA could bind to the promoter region of the SENP6 gene and inhibit SENP6 expression while the regulated SENP6 could in turn modulate the abundance of LANA through desumoylation. This delicate regulation may provide important insights to explain the abundance of LANA during KSHV latency.
引用
收藏
页数:17
相关论文
共 50 条
  • [1] The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen
    Komatsu, T
    Barbera, AJ
    Ballestas, ME
    Kaye, KM
    VIRAL IMMUNOLOGY, 2001, 14 (04) : 311 - 317
  • [2] The latency-associated nuclear antigen, a multifunctional protein central to Kaposi's sarcoma-associated herpesvirus latency
    Ballestas, Mary E.
    Kaye, Kenneth M.
    FUTURE MICROBIOLOGY, 2011, 6 (12) : 1399 - 1413
  • [3] Induction of Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen by the lytic transactivator RTA: A novel mechanism for establishment of latency
    Lan, K
    Kuppers, DA
    Verma, SC
    Sharma, N
    Murakami, M
    Robertson, ES
    JOURNAL OF VIROLOGY, 2005, 79 (12) : 7453 - 7465
  • [4] Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus
    Jeong, JH
    Orvis, J
    Kim, JW
    McMurtrey, CP
    Renne, R
    Dittmer, DP
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (16) : 16822 - 16831
  • [5] Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of kaposi's sarcoma-associated herpesvirus
    Renne, R
    Barry, C
    Dittmer, D
    Compitello, N
    Brown, PO
    Ganem, D
    JOURNAL OF VIROLOGY, 2001, 75 (01) : 458 - 468
  • [6] DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus
    Garber, AC
    Shu, MA
    Hu, JH
    Renne, R
    JOURNAL OF VIROLOGY, 2001, 75 (17) : 7882 - 7892
  • [7] Ribosomal Protein S6 Interacts with the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus
    Chen, Wuguo
    Dittmer, Dirk P.
    JOURNAL OF VIROLOGY, 2011, 85 (18) : 9495 - 9505
  • [8] Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus
    Kedes, DH
    Lagunoff, M
    Renne, R
    Ganem, D
    JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (10): : 2606 - 2610
  • [9] Protein interactions targeting the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus to cell chromosomes
    Krithivas, A
    Fujimuro, M
    Weidner, M
    Young, DB
    Hayward, SD
    JOURNAL OF VIROLOGY, 2002, 76 (22) : 11596 - 11604
  • [10] Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi's sarcoma-associated herpesvirus lytic transcription
    Lu, Fang
    Day, Latasha
    Gao, S. -J.
    Lieberman, Paul M.
    JOURNAL OF VIROLOGY, 2006, 80 (11) : 5273 - 5282