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.

拟议研究的主要目标是阐明宿主先天免疫的机制反应和病毒抗防御反应在表观遗传水平上。真核生物发展了 RNA沉默的机制，以防御侵入性病毒。另一方面，包括感染的病毒人类编码蛋白质，称为病毒抑制剂，以阻止沉默途径逃避宿主监视。关于宿主病毒相互作用的全球范围内研究的重点是转录后基因沉默（PTG）和PTG的病毒抑制。虽然我们对病毒的了解 PTGS水平的抑制已大大扩展，我们对病毒抑制的理解转录基因沉默（TGS）的水平非常差。在真核生物中，核DNA被包裹在组蛋白八聚体形成染色质。染色质甲基不仅调节基因复制和转录，但也控制人和植物中病毒的潜伏期，起作用为先天免疫限制侵入性病原体的系统。 PI小组和其他实验室的最新研究已通过Geminivirus编码的那个陷阱抑制剂，这是一个单链DNA病毒的家族模型有机体拟南芥，基因干扰了TGS途径。通过细胞的蛋白质组学筛选因素，PI组确定了组蛋白甲基转移酶（SUVH4）和组蛋白脱甲基酶（Ref6）TGS途径中的两个关键效应子是陷阱的新真正的善意目标。这些结果和工作来自其他几个小组导致了TGS作为防御机制的模型的概念化捍卫侵入性DNA病原体，而病毒抑制剂可以通过直接抑制 TGS积分器。为了解决该模型，PI提出：1）确定特定的生化基础陷阱对SUVH的抑制作用。 PI希望查明参与的陷阱的关键残基与SUVH4的相互作用并研究残基如何影响SUVH4的功能并改变病毒致病性； PI还将研究陷阱是否针对suvh4的遗传旁系同源物，例如suvh5和 SUVH6调节双子病毒感染； 2）研究陷阱-RF6的功能和机制病毒感染的相互作用。 PI实验室已经观察到REF6与双子病毒染色质结合， REF6的功能丧失突变体显示出对双子病毒感染的敏感性降低。 PI计划系统地研究REF6的生化特征及其在病毒转录中陷阱的功能相互作用和乘法。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调赋予病毒潜伏期，以及DNA病毒如何共同选择将关键的TGS组件劫持为反防御响应。陷阱的抑制机制可能被利用用于定向疗法或预防措施，以解决由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.