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Suppression mechanism of Geminivirus-encoded TrAP protein

双子病毒编码的TrAP蛋白的抑制机制

基本信息

批准号：
10389066
负责人：
Xiuren Zhang
金额：
$ 4.31万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-21 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389066
关键词：
Address Affect Animal Model Arabidopsis Binding Biochemical Chromatin DNA DNA Virus Infections DNA Viruses Defense Mechanisms Disease Epigenetic Process Eukaryota Exhibits Factor V Family Functional disorder Geminiviridae Gene Silencing Gene Silencing Pathway Genes Genetic Genetic Transcription Goals Histones Host Defense Human Immune response Infection Innate Immune Response Innate Immune System Knowledge Laboratories Methylation Modeling Molecular Nuclear Pathogenicity Pathway interactions Physiological Plants Predisposition Preventive measure Proteins Proteomics RNA Interference Race Research Role Single Stranded DNA Virus Viral Virus Virus Diseases Virus Latency Work arm defense response epigenetic silencing histone demethylase histone methyltransferase insight loss of function mutant paralogous gene pathogen screening virus host interaction

项目摘要

The primary goal of the proposed research is to elucidate the mechanism of host innate immune responses and viral counter-defense responses at an epigenetic level. Eukaryotes have evolved sophisticated mechanisms of RNA silencing to defense invasive viruses. On the other hand, viruses including those infecting humans encode proteins, referred to as viral suppressors, to block silencing pathways to evade host surveillance. The prevailing worldwide study on host-virus interaction focuses on the antivirus role of posttranscriptional gene silencing (PTGS) and viral suppression of PTGS. While our knowledge of viral suppression at the PTGS level has been drastically expanded, our understanding of viral suppression at the level of transcriptional gene silencing (TGS) is very poor. In eukaryotes, the nuclear DNA is wrapped onto histone octamers to form a chromatin. Chromatin methylation not only regulates gene replication and transcription, but also controls the latency of viruses in human and plants, functioning as an innate immune system to restrict invasive pathogens. Recent research from the PI's group and other laboratories has illuminated that TrAP suppressor encoded by Geminivirus, a family of single-stranded DNA viruses in the model organism Arabidopsis, genetically interferes with the TGS pathway. By proteomic screening of cellular factors, the PI's group has identified that a histone methyltransferase (SUVH4) and a histone demethylase (REF6), two key effectors in the TGS pathway, are new bona fide targets by TrAP. These results and work from several other groups led to conceptualization of a model that TGS serves as a defense mechanism to defend invasive DNA pathogens, whereas viral suppressors can break this restriction by directly inhibiting the TGS integrators. To address this model, the PI proposes: 1) to determine the biochemical basis for specific inhibitory effect of TrAP on SUVH. The PI wishes to pinpoint the critical residues of TrAP that participate in the interaction with SUVH4 and investigate how the residues affect SUVH4 function and alter the viral pathogenicity; The PI will also study whether TrAP targets the genetic paralogs of SUVH4 such as SUVH5 and SUVH6 to regulate Geminivirus infection; and 2) to investigate function and mechanism of TrAP-REF6 interaction in viral infection. The PI laboratory has observed that REF6 binds to Geminivirus chromatin and loss-of-function mutants of ref6 exhibit reduced susceptibility to Geminivirus infection. The PI plans to systemically study the biochemical features of REF6 and its functional interaction of TrAP in viral transcription and multiplication. The proposed study will address the fundamental but poorly understood mechanism how histone methyltransferases and demethylases coordinately confer viral latency and how DNA virus co-opts to hijack the critical TGS components as counter-defense responses. The suppression mechanism of TrAP may be exploited for directed therapies or preventative measures to address physiological disorders that arise from epigenetic dysfunction in eukaryotes including human.

本研究的主要目的是阐明宿主天然免疫的机制反应和病毒的反防御反应在表观遗传水平。真核生物进化出了复杂的 RNA沉默机制来防御入侵病毒。另一方面，病毒，包括那些感染人类编码称为病毒抑制因子的蛋白质，以阻断沉默途径以逃避宿主监视目前世界范围内对宿主-病毒相互作用的研究主要集中在转录后基因沉默（PTGS）和PTGS的病毒抑制。虽然我们对病毒的了解 PTGS水平的抑制已经大大扩展，我们对PTGS水平的病毒抑制的理解转录基因沉默（TGS）水平非常低。在真核生物中，核DNA被包裹在组蛋白八聚体形成染色质。染色质甲基化不仅调节基因复制，转录，而且还控制病毒在人类和植物中的潜伏期，作为先天免疫功能限制入侵性病原体的系统。PI小组和其他实验室最近的研究表明，阐明了由双生病毒（Geminivirus）编码的TrAP抑制基因，双生病毒是一种单链DNA病毒家族，模式生物拟南芥，遗传干扰TGS途径。通过细胞蛋白质组学筛选， PI的研究小组已经确定，组蛋白甲基转移酶（SUVH 4）和组蛋白去甲基化酶（REF 6），TGS途径中的两个关键效应子，是TrAP的新的真正靶点。这些成果和工作导致TGS作为防御机制的模型概念化，防御侵入性DNA病原体，而病毒抑制剂可以通过直接抑制 TGS积分器。为了解决这一模型，PI提出：1）确定特定的生物化学基础 TrAP对SUVH抑制作用。PI希望确定参与TrAP的关键残基，与SUV H4相互作用，并研究残基如何影响SUV H4功能并改变病毒致病性; PI还将研究TrAP是否针对SUVH 4的遗传旁系同源物，例如SUVH 5和探讨TrAP-REF 6的功能和作用机制病毒感染中的相互作用。PI实验室已经观察到REF 6与双生病毒染色质结合， ref 6的功能丧失突变体表现出对双生病毒感染的易感性降低。PI计划系统研究了REF 6的生物化学特性及其与TrAP在病毒转录中的相互作用和乘法。拟议的研究将解决基本但知之甚少的机制，组蛋白甲基转移酶和脱甲基酶协同赋予病毒潜伏期以及DNA病毒如何选择劫持关键的TGS组件作为反防御反应。TrAP的抑制机制可能用于定向治疗或预防措施，以解决由以下原因引起的生理障碍：包括人类在内的真核生物的表观遗传功能障碍。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In vitro Reconstitution Assays of Arabidopsis 20S Proteasome.

拟南芥 20S 蛋白酶体的体外重建测定。

DOI：
10.21769/bioprotoc.3967
发表时间：
2021
期刊：
Bio-protocol
影响因子：
0.8
作者：
Li,Yanjun;Sun,Di;Yan,Xingxing;Wang,Zhiye;Zhang,Xiuren
通讯作者：
Zhang,Xiuren

Intrinsically disordered proteins SAID1/2 condensate on SERRATE for dual inhibition of miRNA biogenesis in Arabidopsis.

DOI：
10.1073/pnas.2216006120
发表时间：
2023-04-04
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Shang, Baoshuan;Wang, Lin;Yan, Xingxing;Li, Yanjun;Li, Changhao;Wu, Chaohua;Wang, Tian;Guo, Xiang;Choi, Suk Won;Zhang, Tianru;Wang, Ziying;Tong, Chun-Yip;Oh, Taerin;Zhang, Xiao;Wang, Zhiye;Peng, Xu;Zhang, Xiuren
通讯作者：
Zhang, Xiuren

H3.1K27me1 loss confers Arabidopsis resistance to Geminivirus by sequestering DNA repair proteins onto host genome.

DOI：
10.1038/s41467-023-43311-1
发表时间：
2023-11-18
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Wang, Zhen;Castillo-Gonzalez, Claudia M.;Zhao, Changjiang;Tong, Chun-Yip;Li, Changhao;Zhong, Songxiao;Liu, Zhiyang;Xie, Kaili;Zhu, Jiaying;Wu, Zhongshou;Peng, Xu;Jacob, Yannick;Michaels, Scott D.;Jacobsen, Steven E.;Zhang, Xiuren
通讯作者：
Zhang, Xiuren

scInTime: A Computational Method Leveraging Single-Cell Trajectory and Gene Regulatory Networks to Identify Master Regulators of Cellular Differentiation.