二氢喹啉嗪酮化合物RG7834抑制PAPD5 / 7的聚腺苷酸酶功能并加

StephenW

The dihydroquinolizinone compound RG7834 inhibits the polyadenylase function of PAPD5/7 and accelerates the degradation of matured HBV surface protein mRNA
Liren Sun  1 , Fang Zhang  1 , Fang Guo  2 , Fei Liu  2 , Jessie Kulsuptrakul  3 , Andreas Puschnik  3 , Min Gao  2 , Rene Rijnbrand  2 , Michael Sofia  2 , Timothy Block  4 , Tianlun Zhou  4
Affiliations
Affiliations

    1
    Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States.
    2
    Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States.
    3
    Chan Zuckerberg Biohub, 499 Illinois Street, San Francisco, CA 94158, United States.
    4
    Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States [email protected] [email protected].

    PMID: 33046485 DOI: 10.1128/AAC.00640-20

Abstract

Hepatitis B virus (HBV) mRNA metabolism is dependent upon host proteins PAPD5 and PAPD7 (PAPD5/7). PAPD5/7 are cellular, non-canonical, poly(A) polymerases (PAP) whose main function is to oligoadenylate the 3' end of non-coding RNA (ncRNA) for exosome degradation. HBV seems to exploit these two ncRNA quality control factors for viral mRNA stabilization, rather than degradation. RG7834 is a small molecule compound that binds PAPD5/7 and inhibits HBV gene production in both tissue culture and animal study. We reported that RG7834 was able to destabilize multiple HBV mRNA species, ranging from the 3.5 kb pre-genomic/pre-core mRNAs to the 2.4/2.1 kb HBs mRNAs, except for the smallest 0.7 kb HBx mRNA. Compound induced HBV mRNA destabilization was initiated by a shortening of poly(A) tail followed by an accelerated degradation process in both the nucleus and cytoplasm. In cells expressing HBV mRNA, both PAPD5/7 were found to be physically associated with the viral RNA, and the polyadenylating activities of PAPD5/7 were susceptible to RG7834 repression in biochemical assay. Moreover, in PAPD5/7 double knockout cells, viral transcripts with regular length of poly(A) sequence could be initially synthesized but became shortened in hours suggesting that participation of PAPD5/7 in RNA 3' end processing, either during adenosine oligomerization or afterwards, is crucial for RNA stabilization.

Copyright © 2020 American Society for Microbiology.

StephenW

二氢喹啉嗪酮化合物RG7834抑制PAPD5 / 7的聚腺苷酸酶功能并加速成熟HBV表面蛋白mRNA的降解
孙立人1，张方1，方2，刘飞2，杰西·库尔苏普特拉库3，安德烈亚斯·普施尼克3，闵高2，雷内·金布兰德2，迈克尔·索菲亚2，提摩西座4，天伦周4
隶属关系
隶属关系

    1个
    美国宾夕法尼亚州Doylestown，转化医学系Baruch S. Blumberg研究所，宾夕法尼亚州18902。
    2
    Arbutus BioPharma，701退伍军人圈，沃明斯特，宾夕法尼亚州18974，美国。
    3
    Chan Zuckerberg Biohub，伊利诺伊州街499号，旧金山，加利福尼亚州94158，美国。
    4
    美国宾夕法尼亚州Doylestown，转化医学系Baruch S. Blumberg研究所，宾夕法尼亚州18902，美国[email protected] [email protected]。

    PMID：33046485 DOI：10.1128 / AAC.00640-20

抽象

乙型肝炎病毒（HBV）mRNA代谢取决于宿主蛋白PAPD5和PAPD7（PAPD5 / 7）。 PAPD5 / 7是细胞性的，非规范的聚（A）聚合酶（PAP），其主要功能是寡聚腺苷酸化非编码RNA（ncRNA）的3'端，以进行外来体降解。 HBV似乎利用这两个ncRNA质量控制因子来稳定病毒mRNA，而不是降解。 RG7834是一种小分子化合物，可在组织培养和动物研究中与PAPD5 / 7结合并抑制HBV基因的产生。我们报道了RG7834能够使多种HBV mRNA种类不稳定，从3.5 kb基因组前/核心前mRNA到2.4 / 2.1 kb HBs mRNA，除了最小的0.7 kb HBx mRNA。化合物诱导的HBV mRNA失稳是通过缩短poly（A）尾巴开始的，然后在细胞核和细胞质中都加速了降解过程。在表达HBV mRNA的细胞中，发现PAPD5 / 7都与病毒RNA物理相关，在生化分析中，PAPD5 / 7的聚腺苷酸化活性易受RG7834抑制。此外，在PAPD5 / 7双敲除细胞中，可以最初合成具有规则长度的poly（A）序列的病毒转录本，但在数小时内缩短，这表明PAPD5 / 7在腺苷寡聚化过程中或之后参与RNA 3'末端加工。对RNA稳定至关重要。

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乙肝人1949

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