Pathogenesis Mechanism of Geminivirus-Encoded AL2

双生病毒编码的AL2的发病机制

基本信息

批准号：
8416325
负责人：
Xiuren Zhang
金额：
$ 17.84万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416325
关键词：
Address Antiviral Agents Arabidopsis Binding Biological Biological Models Chromatin Complex DNA DNA Viruses Defect Defense Mechanisms Disease Environment Epigenetic Process Eukaryota Event Family Functional disorder Geminiviridae Gene Expression Gene Silencing Genes Goals Health Host Defense Human Immune response Immune system Infection Investigation Knowledge Lead Measures Methylation Modeling Modification Molecular Natural Immunity Pathogenesis Pathway interactions Pharmaceutical Preparations Plants Play Polycomb Predisposition Process Proteins RNA Interference Research Role Signal Transduction Single Stranded DNA Virus System Testing Viral Virus Work base chromatin modification combat defense response gain of function mutation heterochromatin-specific nonhistone chromosomal protein HP-1 human disease infancy insight loss of function novel pathogen research study virus host interaction

项目摘要

DESCRIPTION (provided by applicant): 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. Multi-cellular eukaryotes including humans and plants have evolved sophisticated and fundamental 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 current world-wide 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 still at its infancy. The preliminary studies from the PI's group have illuminated that AL2 suppressor encoded by geminivirus, a family of single-strand DNA viruses, genetically interferes with the pathway of Heterochromatin Protein 1 (HP1) and Polycomb Repressive Complex 2 (PRC2), which are critical genes responsible for epigenetic silencing. Moreover, AL2 biochemically interacts with HP1. These results and work from several other groups led to conceptualization of a model that TGS serves as an innate immune system to restrict invasive DNA pathogens, whereas viral suppressors can break this restriction by directly inhibiting the TGS integrators. The proposed study will address this model: Aim1 will test the hypothesis that HP1/PRC2 is a new line of host antivirus system and AL2 interaction with these components represents a novel counter-defense strategy. Effect of loss-of-function and gain-of-function mutations of HP1/PRC2 genes on modification of geminivirus chromatin will be investigated. Aim 2 will address a speculation that, through interaction with HP1/PRC2, AL2 can reprogram host gene expression and trigger downstream pathogenesis signaling cascades that disrupt host cellular environment leading to disease. A total of 30 AL2-responsive genes have been selected and whether nor not these genes are involved in AL2-elicited pathogenesis processes will be investigated. The proposed study will serve as the starting point for further comprehensive studies on the molecular mechanism of pathogenesis triggered by viral suppressors from the DNA viruses. Understanding these mechanisms will elucidate basic events that occur at the interface between virus and host, and will reveal natural antiviral defense strategies that may be exploited for directed therapies or preventative measures to address health disorders that arise from epigenetic dysfunction in mammalian hosts.

描述（由申请人提供）：拟议研究的主要目标是阐明宿主先天免疫反应的机制和表观遗传学水平的病毒抗防御反应。包括人类和植物在内的多细胞真核生物已将RNA沉默的复杂和基本机制发展为防御入侵病毒。另一方面，包括感染人类的人在内的病毒编码蛋白质（称为病毒抑制剂），以阻止沉默途径逃避宿主监测。当前关于宿主病毒相互作用的全球研究重点是转录后基因沉默（PTGS）和PTG病毒抑制的抗病毒作用。尽管我们在PTGS水平上对病毒抑制的了解已经大大扩展，但我们对转录基因沉默水平（TGS）对病毒抑制的理解仍处于起步阶段。 PI小组的初步研究阐明了由双子链DNA病毒家族编码的Al2抑制剂，遗传干扰了异质染色质蛋白1（HP1）和Polycomb抑制性复合物2（PRC2）的途径，这是负责表观苦味的关键基因。此外，AL2生化与HP1相互作用。这些结果和其他几个组的工作导致了TGS作为先天免疫系统限制侵入性DNA病原体的概念化，而病毒抑制器可以通过直接抑制TGS积分剂来打破这种限制。拟议的研究将解决此模型：AIM1将测试HP1/PRC2是宿主防病毒系统的新系列，而与这些组件的AL2相互作用代表了一种新颖的反防御策略。 HP1/PRC2基因的功能丧失和功能获得突变对GEMINIVIRUS染色质的修饰的影响。 AIM 2将解决一个猜测，即通过与HP1/PRC2的相互作用，AL2可以重新编程宿主基因表达并触发下游发病机理信号传导级联，从而破坏导致疾病的宿主细胞环境。总共选择了30个AL2响应基因，并且将研究这些基因参与AL2引起的发病机理过程。拟议的研究将作为有关由DNA病毒引发的病毒抑制器引发的发病机理的进一步全面研究的起点。了解这些机制将阐明病毒与宿主之间接口上发生的基本事件，并将揭示自然的抗病毒防御策略，这些抗病毒防御策略可能被用于定向疗法或预防措施，以解决哺乳动物宿主中表观遗传功能障碍引起的健康障碍。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Argonautes compete for miR165/166 to regulate shoot apical meristem development.

DOI：
10.1016/j.pbi.2012.05.007
发表时间：
2012-12
期刊：
Current opinion in plant biology
影响因子：
9.5
作者：
Zhang Z;Zhang X
通讯作者：
Zhang X

In vitro Reconstitution Assay of miRNA Biogenesis by Arabidopsis DCL1.

拟南芥 DCL1 的 miRNA 生物发生的体外重建测定。

DOI：
10.21769/bioprotoc.1454
发表时间：
2015
期刊：
Bio-protocol
影响因子：
0.8
作者：
Wang,Tian;Castillo-González,Claudia;You,Lan;Li,Rui;Wen,Liwei;Zhu,Hongliang;Zhang,Xiuren
通讯作者：
Zhang,Xiuren

Spatiotemporal sequestration of miR165/166 by Arabidopsis Argonaute10 promotes shoot apical meristem maintenance.

DOI：
10.1016/j.celrep.2015.02.047
发表时间：
2015-03
期刊：
Cell reports
影响因子：
8.8
作者：
Yuyi Zhou;Minami Honda;Hongliang Zhu;Zhonghui Zhang;Xinwei Guo;Tianhong Li;Zhaohu Li;Xu Peng;
通讯作者：
Yuyi Zhou;Minami Honda;Hongliang Zhu;Zhonghui Zhang;Xinwei Guo;Tianhong Li;Zhaohu Li;Xu Peng;

Arabidopsis Argonaute10 specifically sequesters miR166/165 to regulate shoot apical meristem development.

DOI：
10.1016/j.cell.2011.03.024
发表时间：
2011-04-15
期刊：
Cell
影响因子：
64.5
作者：
Zhu H;Hu F;Wang R;Zhou X;Sze SH;Liou LW;Barefoot A;Dickman M;Zhang X
通讯作者：
Zhang X

Bidirectional processing of pri-miRNAs with branched terminal loops by Arabidopsis Dicer-like1.

DOI：
10.1038/nsmb.2646
发表时间：
2013-09
期刊：
Nature structural & molecular biology
影响因子：
16.8
作者：
Zhu H;Zhou Y;Castillo-González C;Lu A;Ge C;Zhao YT;Duan L;Li Z;Axtell MJ;Wang XJ;Zhang X
通讯作者：
Zhang X