NLR Proteins

NLR 蛋白质类
  • 文章类型: Journal Article
    小麦白粉病是严重危害小麦生产的重要真菌病害,这对食品安全构成了严重威胁。SJ106是一款高品质,抗病春小麦品种;这种抗病性来自小麦-小麦草33。在这项研究中,SJ106抗白粉病基因位于染色体6DS末端,一个新的抗病位点,暂定名为PmSJ106位点。该间隔由包含19个NLR基因的核苷酸结合富含亮氨酸的重复(NLR)基因簇组成。五个NLR是串联重复的基因,和其中之一(卷曲螺旋结构域-核苷酸结合位点-富含亮氨酸的重复序列(CC-NBS-LRR;CNL)型基因,与易感对照相比,TaRGA5样)在SJ106中表达69-836倍。从SJ106扩增了TaRGA5样的基因组DNA和cDNA序列,与易感个体和中国春季相比,它们在LRR区域包含几个核苷酸多态性。过表达TaRGA5样显著提高了易感受体小麦金强5对白粉病的抗性。然而,病毒诱导的TaRGA5样基因沉默(VIGS)仅导致SJ106的抗病性略有下降,可能由其他NLR重复基因补偿。结果表明,TaRGA5样赋予SJ106部分白粉病抗性。作为PmSJ106基因座的成员,TaRGA5样基因与其他NLR重复基因一起发挥作用,以提高小麦对白粉病的抗性。小麦品种SJ106将成为抗白粉病的新型且具有潜在价值的种质。
    Wheat powdery mildew is an important fungal disease that seriously jeopardizes wheat production, which poses a serious threat to food safety. SJ106 is a high-quality, disease-resistant spring wheat variety; this disease resistance is derived from Wheat-wheatgrass 33. In this study, the powdery mildew resistance genes in SJ106 were located at the end of chromosome 6DS, a new disease resistance locus tentatively named PmSJ106 locus. This interval was composed of a nucleotide-binding leucine-rich repeat (NLR) gene cluster containing 19 NLR genes. Five NLRs were tandem duplicated genes, and one of them (a coiled coil domain-nucleotide binding site-leucine-rich repeat (CC-NBS-LRR; CNL) type gene, TaRGA5-like) expressed 69-836-fold in SJ106 compared with the susceptible control. The genome DNA and cDNA sequences of TaRGA5-like were amplified from SJ106, which contain several nucleotide polymorphisms in LRR regions compared with susceptible individuals and Chinese Spring. Overexpression of TaRGA5-like significantly increased resistance to powdery mildew in susceptible receptor wheat Jinqiang5. However, Virus induced gene silence (VIGS) of TaRGA5-like resulted in only a small decrease of SJ106 in disease resistance, presumably compensated by other NLR duplicated genes. The results suggested that TaRGA5-like confers partial powdery mildew resistance in SJ106. As a member of the PmSJ106 locus, TaRGA5-like functioned together with other NLR duplicated genes to improve wheat resistance to powdery mildew. Wheat variety SJ106 would become a novel and potentially valuable germplasm for powdery mildew resistance.
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  • 文章类型: Journal Article
    肌腱炎,以肌腱发炎为特征,由于其多方面的病因和复杂的病理生理学,在诊断和治疗方面都提出了重大挑战。本研究旨在剖析肌腱炎的分子机制。特别关注炎症相关基因及其与免疫系统的相互作用。通过全面的基因表达分析和生物信息学方法,我们确定了不同的炎症基因表达谱,例如NLRP6、NLRP1和MEFV,与免疫检查点分子显著相关,表明在肌腱炎的炎症级联反应中起关键作用。此外,发现MYD88和CD36与HLA家族分子密切相关,强调他们参与免疫应答调节。与预期相反,趋化因子与炎症体基因的相关性最小,提示肌腱炎的非常规炎症途径。转录因子如SP110和CREB5作为炎症体基因的关键调节因子,深入了解肌腱炎的转录控制机制。此外,通过DGidb数据库确定了潜在的治疗靶点,强调可以调节炎性体基因活性的药物,为有针对性的肌腱炎治疗提供新的途径。我们的发现阐明了肌腱炎的复杂分子景观,强调炎性体和免疫相互作用的重要作用,并为开发新的诊断和治疗策略铺平道路。
    Tendinitis, characterized by the inflammation of tendons, poses significant challenges in both diagnosis and treatment due to its multifaceted etiology and complex pathophysiology. This study aimed to dissect the molecular mechanisms underlying tendinitis, with a particular focus on inflammasome-related genes and their interactions with the immune system. Through comprehensive gene expression analysis and bioinformatics approaches, we identified distinct expression profiles of inflammasome genes, such as NLRP6, NLRP1, and MEFV, which showed significant correlations with immune checkpoint molecules, indicating a pivotal role in the inflammatory cascade of tendinitis. Additionally, MYD88 and CD36 were found to be closely associated with HLA family molecules, underscoring their involvement in immune response modulation. Contrary to expectations, chemokines exhibited minimal correlation with inflammasome genes, suggesting an unconventional inflammatory pathway in tendinitis. Transcription factors like SP110 and CREB5 emerged as key regulators of inflammasome genes, providing insight into the transcriptional control mechanisms in tendinitis. Furthermore, potential therapeutic targets were identified through the DGidb database, highlighting drugs that could modulate the activity of inflammasome genes, offering new avenues for targeted tendinitis therapy. Our findings elucidate the complex molecular landscape of tendinitis, emphasizing the significant role of inflammasomes and immune interactions, and pave the way for the development of novel diagnostic and therapeutic strategies.
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  • 文章类型: Journal Article
    保护蛋白在感知病原体编码的毒力因子时启动防御机制。成功的病毒病原体可能抑制保护蛋白活性,但是这些相互作用在很大程度上是不确定的。这里,我们证明,人类病原体单纯疱疹病毒1(HSV-1)刺激和抑制由NLRP1启动的抗病毒途径,NLRP1是一种保护蛋白,在激活时诱导炎症体形成和焦化性细胞死亡。值得注意的是,人角质形成细胞的HSV-1感染促进对NLRP1的翻译后修饰,与MAPK依赖性NLRP1激活一致,但不会导致下游炎症小体的形成。我们将感染的细胞蛋白0(ICP0)鉴定为关键的HSV-1蛋白,该蛋白是抑制NLRP1途径所必需和足够的。机械上,ICP0的细胞质定位和作为E3泛素连接酶的功能可防止自抑制性NT-NLRP1片段的蛋白酶体降解,从而防止炎症小体的形成。Further,我们证明了抑制该炎症小体对于促进HSV-1复制是重要的。因此,我们已经建立了HSV-1克服人类守卫介导的抗病毒防御策略的机制。
    Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0\'s cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.
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  • 文章类型: Journal Article
    NLR家族蛋白充当细胞内受体。基因复制放大了NLR基因的数量,随后的突变偶尔会对第二个基因进行修饰,从而有益于免疫。然而,基因复制后的进化过程以及复制的NLR之间的功能关系仍不清楚。这里,我们报道了水稻NLR蛋白Pit1与其旁系物Pit2相关。两者是抗稻瘟病菌所必需的,但具有不同的功能:Pit1诱导细胞死亡,而Pit2竞争性抑制Pit1介导的细胞死亡。在进化过程中,Pit2对Pit1的抑制可能是通过对Pit2的NB-ARC结构域中的两个命运决定残基的阳性选择而产生的,这解释了Pit1和Pit2之间的功能差异。因此,Pit2失去了其质膜定位,但获得了干扰细胞溶质中Pit1的新功能。这些发现阐明了基因复制后串联复制的NLR基因的进化轨迹。
    NLR family proteins act as intracellular receptors. Gene duplication amplifies the number of NLR genes, and subsequent mutations occasionally provide modifications to the second gene that benefits immunity. However, evolutionary processes after gene duplication and functional relationships between duplicated NLRs remain largely unclear. Here, we report that the rice NLR protein Pit1 is associated with its paralogue Pit2. The two are required for the resistance to rice blast fungus but have different functions: Pit1 induces cell death, while Pit2 competitively suppresses Pit1-mediated cell death. During evolution, the suppression of Pit1 by Pit2 was probably generated through positive selection on two fate-determining residues in the NB-ARC domain of Pit2, which account for functional differences between Pit1 and Pit2. Consequently, Pit2 lost its plasma membrane localization but acquired a new function to interfere with Pit1 in the cytosol. These findings illuminate the evolutionary trajectory of tandemly duplicated NLR genes after gene duplication.
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  • 文章类型: Journal Article
    大豆抗病1(GmDR1)的过表达表现出对镰刀菌的广谱抗性,异端甘氨酸(大豆胞囊线虫),荨麻疹(Koch)(蜘蛛螨),和大豆中的Aphis甘氨酸Matsumura(大豆蚜虫)。为了了解GmDR1介导的广谱免疫的机制,用几丁质处理后的强和弱GmDR1过表达的转录组,这些生物常见的病原体和害虫相关分子模式(PAMP),被调查了。强和弱的GmDR1过表达显示6098和992个基因的表达改变,分别,与几丁质处理后的非转基因对照相比。然而,与对照相比,只有192个几丁质和115个缓冲响应基因在强和弱GmDR1过表达基因中的表达水平变化超过两倍。MapMan分析192个几丁质响应基因揭示了64个生物胁迫相关基因,与对照组相比,其中53例被诱导,11例被抑制。这53个几丁质诱导的基因包括9个编码受体激酶的基因,13编码核苷酸结合富含亮氨酸的重复序列(NLR)受体蛋白,七个编码WRKY转录因子,四个乙烯响应因素,和三个MYB样转录因子。对这些基因的一个子集的研究揭示了三种受体蛋白激酶,七种NLR蛋白,和一个WRKY转录因子基因在F.virguliforme和H.glycines感染后诱导。整合的质膜GmDR1蛋白最有可能识别PAMPs,包括几丁质,并激活编码受体激酶的基因的转录,NLR蛋白和防御相关基因。GmDR1可能是一种模式识别受体,可调节几种NLR的表达,以表达PAMP触发的免疫和/或引发效应子触发的免疫。
    Overexpression of Glycine max disease resistant 1 (GmDR1) exhibits broad-spectrum resistance against Fusarium virguliforme, Heterodera glycines (soybean cyst nematode), Tetranychus urticae (Koch) (spider mites), and Aphis glycines Matsumura (soybean aphids) in soybean. To understand the mechanisms of broad-spectrum immunity mediated by GmDR1, the transcriptomes of a strong and a weak GmDR1-overexpressor following treatment with chitin, a pathogen- and pest-associated molecular pattern (PAMP) common to these organisms, were investigated. The strong and weak GmDR1-overexpressors exhibited altered expression of 6098 and 992 genes, respectively, as compared to the nontransgenic control following chitin treatment. However, only 192 chitin- and 115 buffer-responsive genes exhibited over two-fold changes in expression levels in both strong and weak GmDR1-overexpressors as compared to the control. MapMan analysis of the 192 chitin-responsive genes revealed 64 biotic stress-related genes, of which 53 were induced and 11 repressed as compared to the control. The 53 chitin-induced genes include nine genes that encode receptor kinases, 13 encode nucleotide-binding leucine-rich repeat (NLR) receptor proteins, seven encode WRKY transcription factors, four ethylene response factors, and three MYB-like transcription factors. Investigation of a subset of these genes revealed three receptor protein kinases, seven NLR proteins, and one WRKY transcription factor genes that are induced following F. virguliforme and H. glycines infection. The integral plasma membrane GmDR1 protein most likely recognizes PAMPs including chitin and activates transcription of genes encoding receptor kinases, NLR proteins and defense-related genes. GmDR1 could be a pattern recognition receptor that regulates the expression of several NLRs for expression of PAMP-triggered immunity and/or priming the effector triggered immunity.
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  • 文章类型: Journal Article
    在植物中,核苷酸结合位点和富含亮氨酸的重复蛋白(NLR)在效应子触发免疫(ETI)中起关键作用。然而,NLR介导的抗病潜在的确切机制仍然难以捉摸.先前的研究表明,NLR基因对Pik-H4通过与转录因子OsBIHD1相互作用而赋予稻瘟病抗性,从而导致激素途径的上调。在本研究中,我们鉴定了RNA识别基序(RRM)蛋白,OsRRM2,在囊泡和叶绿体中与Pik1-H4和Pik2-H4相互作用。OsRRM2通过上调抗性基因和与叶绿体免疫相关的基因对Pik-H4介导的水稻稻瘟病抗性表现出适度的影响。此外,通过指数富集使用配体的系统进化来阐明OsRRM2的RNA结合序列。转录组分析进一步表明OsRRM2促进叶绿体基因ndhB的RNA编辑。总的来说,我们的发现揭示了一种促进NLR基因对易位并调节叶绿体免疫的叶绿体RRM蛋白,从而弥合ETI和叶绿体免疫之间的差距。
    In plants, nucleotide-binding site and leucine-rich repeat proteins (NLRs) play pivotal roles in effector-triggered immunity (ETI). However, the precise mechanisms underlying NLR-mediated disease resistance remain elusive. Previous studies have demonstrated that the NLR gene pair Pik-H4 confers resistance to rice blast disease by interacting with the transcription factor OsBIHD1, consequently leading to the upregulation of hormone pathways. In the present study, we identified an RNA recognition motif (RRM) protein, OsRRM2, which interacted with Pik1-H4 and Pik2-H4 in vesicles and chloroplasts. OsRRM2 exhibited a modest influence on Pik-H4-mediated rice blast resistance by upregulating resistance genes and genes associated with chloroplast immunity. Moreover, the RNA-binding sequence of OsRRM2 was elucidated using systematic evolution of ligands by exponential enrichment. Transcriptome analysis further indicated that OsRRM2 promoted RNA editing of the chloroplastic gene ndhB. Collectively, our findings uncovered a chloroplastic RRM protein that facilitated the translocation of the NLR gene pair and modulated chloroplast immunity, thereby bridging the gap between ETI and chloroplast immunity.
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  • 文章类型: Journal Article
    核苷酸结合域和富含亮氨酸的重复序列(NLR)免疫受体基因构成了植物的主要防线,同时作用于病原体识别和抗性机制激活。据报道,NLR在松木松树(Pinusflexilis)中形成大的基因簇,但尚不清楚这种基因组结构在针叶树(Pinophyta)的现存物种中的广泛分布。我们使用比较基因组分析来评估丰度的模式,NLR基因的多样性和基因组分布。松科的染色体水平全基因组组装和高密度连锁图谱,柏科,使用现有和定制的管道扫描紫杉科和其他裸子植物的NLR基因。将发现的基因跨染色体和连锁群定位,并对进化史进行系统发育分析。针叶树基因组的特征是NLR基因的密集簇,高度定位在一条染色体上。这些簇富含TNL编码基因,这似乎是通过多个串联复制事件形成的。与被子植物和非针叶裸子植物相比,NLR基因的基因组聚类在针叶树中普遍存在。NLR密集的基因组区域可能会影响植物的大部分抗性,通过育种告知我们对适应生物胁迫和遗传资源开发的理解。
    Nucleotide-binding domain and leucine-rich repeat (NLR) immune receptor genes form a major line of defense in plants, acting in both pathogen recognition and resistance machinery activation. NLRs are reported to form large gene clusters in limber pine (Pinus flexilis), but it is unknown how widespread this genomic architecture may be among the extant species of conifers (Pinophyta). We used comparative genomic analyses to assess patterns in the abundance, diversity, and genomic distribution of NLR genes. Chromosome-level whole genome assemblies and high-density linkage maps in the Pinaceae, Cupressaceae, Taxaceae, and other gymnosperms were scanned for NLR genes using existing and customized pipelines. The discovered genes were mapped across chromosomes and linkage groups and analyzed phylogenetically for evolutionary history. Conifer genomes are characterized by dense clusters of NLR genes, highly localized on one chromosome. These clusters are rich in TNL-encoding genes, which seem to have formed through multiple tandem duplication events. In contrast to angiosperms and nonconiferous gymnosperms, genomic clustering of NLR genes is ubiquitous in conifers. NLR-dense genomic regions are likely to influence a large part of the plant\'s resistance, informing our understanding of adaptation to biotic stress and the development of genetic resources through breeding.
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  • 文章类型: Editorial
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  • 文章类型: Journal Article
    非西班牙裔黑人(NHB)的阿尔茨海默病(AD)患病率是非西班牙裔白人(NHW)的两倍。这项研究的目的是确定印记控制区(ICR)的异常甲基化是否与AD相关。从来自9个AD(5个NHB和4个NHW)和8个对照(4个NHB和4个NHW)的脑组织的全基因组亚硫酸氢盐测序DNA中生物信息学鉴定了差异甲基化区域(DMRs)。我们确定了位于120个区域内的DMR,这些区域被定义为人类印记组中的候选ICR(https://基因组。ucsc.edu/s/imprintome/hg38。AD.Brain_track)。81个ICR在NHB-AD中差异甲基化,27个ICRs在NHW-AD中差异甲基化,两个群体共同的两个区域靠近炎症小体基因,NLRP1和一个已知的印迹基因,MEST/MESTIT1。这些发现表明,调节基因组印记的区域DNA甲基化的早期发育改变可能导致AD风险,并且NHB和NHW之间的这种表观遗传风险不同。
    Alzheimer\'s disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome ( https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain_track ). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs.
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  • 文章类型: Journal Article
    NLRP炎性体是一组胞质多蛋白寡聚体模式识别受体(PRR),参与识别由感染细胞产生的病原体相关分子模式(PAMP)和危险相关分子模式(DAMP)。它们通过触发保护性炎症反应来调节先天免疫。然而,尽管有保护作用,NLRP传感蛋白中的异常NLPR炎性体激活和功能获得突变参与非通信自身免疫的发生和增强,自身炎症,和神经退行性疾病。在过去的几年里,在理解NLRP炎性体生理功能及其激活的分子机制方面取得了重大进展,以及针对炎症性疾病中NLRP炎性体活性的疗法。这里,我们提供了NLRP炎性体的最新研究进展,包括NLRP1、CARD8、NLRP3、NLRP6、NLRP7、NLRP2、NLRP9、NLRP10和NLRP12关于它们的结构和组装特征,信号转导和分子激活机制。重要的是,我们强调了与许多人类自身炎症相关的NLRP炎性体失调的机制,自身免疫,和神经退行性疾病。总的来说,我们总结了NLRP生物学的最新发现,它们形成的炎性体,以及它们在健康和疾病中的作用,并为NLRP炎性体的未来研究提供治疗策略和观点。
    NLRP inflammasomes are a group of cytosolic multiprotein oligomer pattern recognition receptors (PRRs) involved in the recognition of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) produced by infected cells. They regulate innate immunity by triggering a protective inflammatory response. However, despite their protective role, aberrant NLPR inflammasome activation and gain-of-function mutations in NLRP sensor proteins are involved in occurrence and enhancement of non-communicating autoimmune, auto-inflammatory, and neurodegenerative diseases. In the last few years, significant advances have been achieved in the understanding of the NLRP inflammasome physiological functions and their molecular mechanisms of activation, as well as therapeutics that target NLRP inflammasome activity in inflammatory diseases. Here, we provide the latest research progress on NLRP inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRP7, NLRP2, NLRP9, NLRP10, and NLRP12 regarding their structural and assembling features, signaling transduction and molecular activation mechanisms. Importantly, we highlight the mechanisms associated with NLRP inflammasome dysregulation involved in numerous human auto-inflammatory, autoimmune, and neurodegenerative diseases. Overall, we summarize the latest discoveries in NLRP biology, their forming inflammasomes, and their role in health and diseases, and provide therapeutic strategies and perspectives for future studies about NLRP inflammasomes.
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