更新于：2024-11-01

PCBP2

更新于：2024-11-01

基本信息

别名

Alpha-CP2、Heterogeneous nuclear ribonucleoprotein E2、hnRNP E2

+ [6]

简介

Single-stranded nucleic acid binding protein that binds preferentially to oligo dC (PubMed:7607214, PubMed:12414943). Major cellular poly(rC)-binding protein (PubMed:12414943). Binds also poly(rU) (PubMed:12414943). Acts as a negative regulator of antiviral signaling (PubMed:19881509, PubMed:35322803). Negatively regulates cellular antiviral responses mediated by MAVS signaling (PubMed:19881509). It acts as an adapter between MAVS and the E3 ubiquitin ligase ITCH, therefore triggering MAVS ubiquitination and degradation (PubMed:19881509). Negativeley regulates the cGAS-STING pathway via interaction with CGAS, preventing the formation of liquid-like droplets in which CGAS is activated (PubMed:35322803). Together with PCBP1, required for erythropoiesis, possibly by regulating mRNA splicing (By similarity). (Microbial infection) In case of infection by poliovirus, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation (PubMed:12414943, PubMed:24371074). Also plays a role in initiation of viral RNA replication in concert with the viral protein 3CD (PubMed:12414943).

关联

项与 PCBP2 相关的药物

siRNA(UMKC)

靶点

PCBP2

作用机制

PCBP2 inhibitors

在研机构

University of Missouri-Kansas City

原研机构-

在研适应症

酒精性肝疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PCBP2 相关的临床结果

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100 项与 PCBP2 相关的转化医学

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0 项与 PCBP2 相关的专利（医药）

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292

项与 PCBP2 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Overexpression of long noncoding RNA DUXAP8 inhibits ER-phagy through activating AKT/mTOR signaling and contributes to preeclampsia

Article

作者: Xu, Qin ; Zhou, Rong ; Gao, Lin-Bo ; Yin, Yang-Xue ; Liu, Min ; Xie, Shuang-Shuang ; Liao, Ling-Yun ; Chen, Hong-Qin ; Wei, Xiao-Hong

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.

2024-10-14·Nucleic Acids Research

Structural basis for a highly conserved RNA-mediated enteroviral genome replication

Article

作者: Koirala, Deepak ; Das, Naba Krishna ; Vogt, Jeff ; Patel, Alisha ; Banna, Hasan Al

AbstractEnteroviruses contain conserved RNA structures at the extreme 5′ end of their genomes that recruit essential proteins 3CD and PCBP2 to promote genome replication. However, the high-resolution structures and mechanisms of these replication-linked RNAs (REPLRs) are limited. Here, we determined the crystal structures of the coxsackievirus B3 and rhinoviruses B14 and C15 REPLRs at 1.54, 2.2 and 2.54 Å resolution, revealing a highly conserved H-type four-way junction fold with co-axially stacked sA-sD and sB-sC helices that are stabilized by a long-range A•C•U base-triple. Such conserved features observed in the crystal structures also allowed us to predict the models of several other enteroviral REPLRs using homology modeling, which generated models almost identical to the experimentally determined structures. Moreover, our structure-guided binding studies with recombinantly purified full-length human PCBP2 showed that two previously proposed binding sites, the sB-loop and 3′ spacer, reside proximally and bind a single PCBP2. Additionally, the DNA oligos complementary to the 3′ spacer, the high-affinity PCBP2 binding site, abrogated its interactions with enteroviral REPLRs, suggesting the critical roles of this single-stranded region in recruiting PCBP2 for enteroviral genome replication and illuminating the promising prospects of developing therapeutics against enteroviral infections targeting this replication platform.

2024-09-19·Veterinary research

Duck hepatitis A virus utilizes PCBP2 to facilitate viral translation and replication.

Article

作者: Cheng, Anchun ; Wang, Mingshu ; Chen, Shun ; Jiang, Yurui ; Sun, Di ; Wu, Ying ; He, Yu ; Zhang, Wei ; Tian, Bin ; Yang, Qiao ; Xu, Chenxia ; Ou, Xumin ; Wu, Zhen ; Zhu, Dekang ; Zhao, Xinxin ; Jia, Renyong ; Liu, Mafeng ; Huang, Juan ; Zhang, Shaqiu

Duck hepatitis A virus type 1 (DHAV-1) is an important member of the Picornaviridae family that causes highly fatal hepatitis in ducklings. Since picornaviruses have small genomes with limited coding capacity, they must utilize host proteins for viral cap-independent translation and RNA replication. Here, we report the role of duck poly(rC)-binding protein 2 (PCBP2) in regulating the replication and translation of DHAV-1. During DHAV-1 infection, PCBP2 expression was upregulated. A biotinylated RNA pull-down assay revealed that PCBP2 positively regulates DHAV-1 translation through specific interactions with structural domains II and III of the DHAV-1 internal ribosome entry site (IRES). Further studies revealed that PCBP2 promotes DHAV-1 replication via an interaction of its KH1 domain (aa 1-92) with DHAV-1 3D^pol. Thus, our studies demonstrated the specific role of PCBP2 in regulating DHAV-1 translation and replication, revealing a novel mechanism by which host‒virus interactions regulate viral translation and replication. These findings contribute to further understanding of the pathogenesis of picornavirus infections.

项与 PCBP2 相关的新闻（医药）

2024-09-03

·生物探索

Nat Chem | 陈加余团队系统揭示三链体DNA互作蛋白调控机制与功能多样性

引言 DNA右手双螺旋结构的提出开启了分子生物学新篇章【1】。事实上，除右手双螺旋结构外，还存在其他非经典DNA构象，如三链体DNA（triplex DNA）。三链体DNA是由单链DNA通过胡斯坦氢键（Hoogsteen hydrogen bonds）与双链DNA的大沟特异性结合形成的一种三链结构【2】。该结构在基因组中广泛分布，发挥重要的基因调控作用，并可导致基因组不稳定性。基于以上功能，三链体形成寡核苷酸（triplex forming oligonucleotides）既是调节基因表达，诱导突变、重组和凋亡的分子工具，又在定点交联顺铂药物【3】和特异性杀伤原癌基因扩增的癌细胞【4】等方面展示出巨大应用价值，具备成为新型核酸药物的潜力。然而，关于细胞内三链体DNA动态的调控网络与分子机制尚未得到充分解析，极大阻碍了三链体DNA的基础研究与转化应用。 2024年9月2日，南京大学陈加余课题组在Nature Chemistry杂志发表了题为“Chemoproteomic profiling unveils binding and functional diversity of endogenous proteins that interact with endogenous triplex DNA”的研究论文，首次系统性揭示了内源性三链体DNA互作蛋白及其多样化的调控模式与分子功能【5】。当前，三链体DNA调控蛋白的发现及其分子机制解析主要依赖体外实验，其准确性和可推广性有待商榷。为实现在活细胞中系统捕获内源三链体DNA互作蛋白，作者开发了特异性识别三链体DNA的光交联化学探针photoBQQ。该探针在Benzoquinoquinoxaline（BQQ）分子的基础上增加了双吖丙啶（diazirine）和炔基（alkyne）基团。双吖丙啶具有紫外光交联活性，而炔基基团可通过点击化学反应连接生物素，以便后续富集。作者通过一系列体外和体内实验证实了photoBQQ探针对三链体DNA的特异性识别能力及其对三链体DNA调控蛋白的临近标记活性。利用该探针，作者在HeLa和A549细胞系中开展了化学蛋白质组学研究，特异性捕获并通过定量质谱成功鉴定了78个高置信度的三链体DNA互作蛋白，为理解三链体DNA的动态调控机制奠定了坚实基础。随后，作者通过多组学数据（ChIP-seq，CUT&Tag，S1-END-seq等）的联合分析揭示了这些调控蛋白的分子调控机制及潜在生物学功能。作者对这些蛋白的DNA结合位点与三链体DNA形成区域进行了系统比对，识别出三种截然不同的结合模式（图1）。不同结合模式对应不同的调控机制和生物学过程。值得注意的是，先前研究难以区分内源性三链体DNA的构型，而该研究通过分析单链多聚胞苷酸结合蛋白HNRNPK、PCBP1和PCBP2的结合模式，推断出内源性三链体DNA主要采用H-r3构型。该重要发现也解决了HNRNPK、PCBP1和PCBP2蛋白的DNA结合位点相较于其RNA结合位点存在偏移的这一领域内悬而未决的难题【6】。此外，HNRNPK、PCBP1和PCBP2蛋白的转录调控功能或许也与其结合内源性三链体DNA的活性密切相关【7】。图1 – 三链体DNA调控蛋白的不同结合模式(Credit: Nature Chemistry) 最后，作者以新发现的三链体DNA调控蛋白DDX3X为例，进行了深入的分子机制研究。通过体外解旋酶实验，作者发现DDX3X能够以不依赖ATP的方式解旋三链体DNA，并且尤其偏好第三链5′端存在额外单链DNA（5′ overhang）的三链体DNA。据作者了解，DDX3X是迄今为止发现的唯一一个ATP非依赖的三链体DNA解旋酶。进一步的免疫荧光实验显示，DDX3X缺失会导致三链体DNA的累积并诱发DNA损伤。通过CUT&Tag实验，作者发现DDX3X调控的三链体DNA与DNA损伤位点高度共定位。最后，通过连接介导的PCR实验（LM-PCR）证实，DDX3X缺失导致DNA损伤的分子机制是三链体DNA区域发生双链断裂（图2）。这些发现为理解 DDX3X 在各种生理过程和疾病中的分子机制提供了新思路。总之，该研究首次系统地揭示了内源性三链体DNA调控蛋白的全景图，不仅为深入理解三链体DNA的动态调控奠定了基础，也为诸多蛋白的分子功能研究提供了全新视角。这一研究还为探索三链体DNA的生物学功能及其在转化医学中的应用提供了宝贵资源。图2 – 化学蛋白质组学鉴定到的DDX3X通过解旋三链体DNA防止DNA损伤(Credit: Nature Chemistry) 参考文献 1 Watson, J. D. & Crick, F. H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171, 737-738 (1953). https://doi.org:10.1038/171737a0 2 Frank-Kamenetskii, M. D. & Mirkin, S. M. Triplex DNA structures. Annu Rev Biochem 64, 65-95 (1995). https://doi.org:10.1146/annurev.bi.64.070195.000433 3 Hennessy, J. et al. A Click Chemistry Approach to Targeted DNA Crosslinking with cis-Platinum(II)-Modified Triplex-Forming Oligonucleotides. Angew Chem Int Ed Engl 61, e202110455 (2022). https://doi.org:10.1002/anie.202110455 4 Kaushik Tiwari, M. et al. Direct targeting of amplified gene loci for proapoptotic anticancer therapy. Nat Biotechnol 40, 325-334 (2022). https://doi.org:10.1038/s41587-021-01057-5 5 Xu, H. et al. Chemoproteomic profiling unveils binding and functional diversity of endogenous proteins that interact with endogenous triplex DNA. Nat Chem (2024). https://doi.org:10.1038/s41557-024-01609-7 6 Van Nostrand, E. L. et al. A large-scale binding and functional map of human RNA-binding proteins. Nature 583, 711-719 (2020). https://doi.org:10.1038/s41586-020-2077-3 7 Xiao, R. et al. Pervasive Chromatin-RNA Binding Protein Interactions Enable RNA-Based Regulation of Transcription. Cell 178, 107-121 e118 (2019). https://doi.org:10.1016/j.cell.2019.06.001 https://www.nature.com/articles/s41557-024-01609-7 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

核酸药物寡核苷酸