更新于：2024-11-01

PLOD1

更新于：2024-11-01

基本信息

别名

LH1、LLH、Lysyl hydroxylase 1

+ [3]

简介

Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils (By similarity). Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens (PubMed:8621606, PubMed:10686424, PubMed:15854030). These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links (Probable).

关联

靶点

PLOD1

作用机制

PLOD1 modulators

在研机构

UMass Chan Medical School

原研机构

UMass Chan Medical School

在研适应症

Ehlers-Danlos综合征

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 PLOD1 相关的临床结果

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100 项与 PLOD1 相关的转化医学

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0 项与 PLOD1 相关的专利（医药）

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650

项与 PLOD1 相关的文献（医药）

2024-11-01·Matrix Biology

Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction

Article

作者: Elliott, Erin M ; Singhal, Richa A ; Aebersold, Julia ; Leask, Andrew ; Moore Iv, Joseph B ; Garrett, Lauren ; Fischer, Annalara G ; Nong, Yibing ; Brittian, Kenneth R ; Jones, Steven P ; Sadri, Ghazal

BACKGROUNDMembers of the cellular communication network family (CCN) of matricellular proteins, like CCN1, have long been implicated in the regulation of cellular processes underlying wound healing, tissue fibrogenesis, and collagen dynamics. While many studies suggest antifibrotic actions for CCN1 in the adult heart through the promotion of myofibroblast senescence, they largely relied on exogenous supplementation strategies in in vivo models of cardiac injury where its expression is already induced-which may confound interpretation of its function in this process. The objective of this study was to interrogate the role of the endogenous protein on fibroblast function, collagen structural dynamics, and its associated impact on cardiac fibrosis after myocardial infarction (MI).METHODS/RESULTSHere, we employed CCN1 loss-of-function methodologies, including both in vitro siRNA-mediated depletion and in vivo fibroblast-specific knockout mice to assess the role of the endogenous protein on cardiac fibroblast fibrotic signaling, and its involvement in acute scar formation after MI. In vitro depletion of CCN1 reduced cardiac fibroblast senescence and proliferation. Although depletion of CCN1 decreased the expression of collagen processing and stabilization enzymes (i.e., P4HA1, PLOD1, and PLOD2), it did not inhibit myofibroblast induction or type I collagen synthesis. Alone, fibroblast-specific removal of CCN1 did not negatively impact ventricular performance or myocardial collagen content but did contribute to disorganization of collagen fibrils and increased matrix compliance. Similarly, Ccn1 ablated animals subjected to MI showed no discernible alterations in cardiac structure or function one week after permanent coronary artery ligation, but exhibited marked increases in incidence of mortality and cardiac rupture. Consistent with our findings that CCN1 depletion does not assuage myofibroblast conversion or type I collagen synthesis in vitro, Ccn1 knockout animals revealed no measurable differences in collagen scar width or mass compared to controls; however, detailed structural analyses via SHG and TEM of scar regions revealed marked alterations in their scar collagen topography-exhibiting changes in numerous macro- and micro-level collagen architectural attributes. Specifically, Ccn1 knockout mice displayed heightened ECM structural complexity in post-MI scar regions, including diminished local alignment and heightened tortuosity of collagen fibers, as well as reduced organizational coherency, packing, and size of collagen fibrils. Associated with these changes in ECM topography with the loss of CCN1 were reductions in fibroblast-matrix interactions, as evidenced by reduced fibroblast nuclear and cellular deformation in vivo and reduced focal-adhesion formation in vitro; findings that ultimately suggest CCN1's ability to influence fibroblast-led collagen alignment may in part be credited to its capacity to augment fibroblast-matrix interactions.CONCLUSIONSThese findings underscore the pivotal role of endogenous CCN1 in the scar formation process occurring after MI, directing the appropriate arrangement of the extracellular matrix's collagenous components in the maturing scar-shaping the mechanical properties that support its structural stability. While this suggests an adaptive role for CCN1 in regulating collagen structural attributes crucial for supporting scar integrity post MI, the long-term protracted expression of CCN1 holds maladaptive implications, potentially diminishing collagen structural complexity and compliance in non-infarct regions.

2024-11-01·Plant Physiology and Biochemistry

Monitoring molecular events during photo-driven ubiquinone pool reduction in PufX+ and PufX− membranes from Rhobobacter capsulatus by time-resolved FTIR difference spectroscopy

Article

作者: Beatty, J. Thomas ; Johnson, Jeanette A. ; Johnson, Jeanette A ; Mezzetti, Alberto ; Beatty, J Thomas ; Leibl, Winfried

The PufX protein is found in the photosynthetic membranes of several purple bacteria and is involved in ubiquinol-ubiquinone exchange at the Q_B site of the reaction center. We have studied quinone pool reduction in chromatophores from PufX⁺ and PufX^- strains of Rhodobacter capsulatus by time-resolved FTIR difference spectroscopy under and after continuous illumination. To our knowledge, it is the first time that quinone pool reduction has been directly followed in real time in Rba. capsulatus membranes. Thanks to the availability in the literature of IR marker bands for protein conformational changes, ubiquinone consumption, ubiquinol production, Q---QH₂ quinhydrone complex formation, as well as for RC-bound Q_A^- and Q_B^- semiquinone species, it is possible to follow all the molecular events associated with light-induced quinone pool reduction. In Rba. capsulatus PufX ⁺ chromatophores, these events resemble the ones found in Rba. sphaeroides wild-type membranes. In PufX^- chromatophores the situation is different. Spectra recorded during 22.7 s of illumination showed a much smaller amount of photoreduced quinol, consistent with previous observations that PufX is required for efficient QH₂^/Q exchange at the Q_B site of the RC. Q consumption and QH₂ formation are rapidly associated with Q_A^- formation, showing that the structure of the RC-LH1 complex in PufX^- membranes does not provide efficient access to the Q_B site of the RC to a large fraction of the quinone pool, evidently because the LH1 ring increases in size to impair access to the RC. The presence of a positive band at 1560 cm^-1 suggests also the transient formation, in a fraction of chromatophores or of RC-LH1 complexes, of a Q---QH₂ quinhydrone complex. Experiments carried out after 2-flash and 10-flash sequences make it possible to estimate that the size of the quinone pool with access to the Q_B site in PufX^- membranes is ≥ 5 ubiquinone molecules per RC. The results are discussed in the framework of the current knowledge of protein organization and quinone pool reduction in bacterial photosynthetic membranes.

2024-11-01·Genomics

PLOD1 promote proliferation and migration with glycolysis via the Wnt/β-catenin pathway in THCA

Article

作者: Hao, Zhanyu ; Liu, Jianing ; Sun, Jingfu ; Cong, Wei ; Gong, Maosong

THCA (Thyroid carcinoma) is the most common endocrine malignancy in the world. The PLOD1 is highly expressed in THCA, but the mechanism is still unclear. It is found that the cell proliferation and migration were inhibited in si-PLOD1 group, and promoted with PLOD1 overexpression. MAZ is the transcription factor of PLOD1. The cell activities induced MAZ were reversed by si-PLOD1. The Glucose uptake, lactate production and ATP/ADP ratio were decreased with si-PLOD1. The glycolysis related proteins GLUT1, HK2, PFKP, PKM2, LDHA and Wnt/β-catenin pathway proteins WNT5A, cyclin D1, β-catenin were inhibited, GSK-3β is increased in si-PLOD1 group. BML-284 could reversed the si-PLOD1 effects on cell activities and Wnt/β-catenin pathway. The tumor xenografts were inhibited in si-PLOD1 group. As a potential therapeutic target, PLOD1 is regulated by MAZ in THCA. PLOD1 depletion could inhibit THCA cell proliferation and metastasis by glycolysis, which is inhibited by Wnt/β-catenin pathway in THCA.

项与 PLOD1 相关的新闻（医药）

2024-02-20

·Science Daily

Photosynthetic mechanism of purple sulfur bacterium adapted to low-calcium environments

Purple sulfur bacteria (PSB) convert light energy into chemical energy through photosynthesis. Interestingly, certain species can photosynthesize even in environments with low-calcium levels. Using cryo-electron microscopy, researchers unveiled the structure of light-harvesting complexes and elucidated the mechanism that facilitates photosynthesis under low-calcium conditions. Photosynthetic bacteria, unlike plants, do not generate oxygen as a photosynthetic byproduct because they use hydrogen sulfide instead of water to convert solar energy into chemical energy (electrons). This process is orchestrated by a protein complex, the light-harvesting 1-reaction center (LH1-RC). Numerous PSB thrive in calcium-rich environments, such as hot springs and seawater. In the three-dimensional LH1-RC structure, the LH1 antenna protein is typically associated with calcium. However, the photosynthetic mechanism remains elusive in Allochromatium vinosum, a model species of autotrophic bacteria capable of thriving in low-calcium or soft-water environments, as hypothetically, calcium is not involved in the photosynthetic process in this model. Using cryo-electron microscopy, the researchers revealed the LH1-RC structures of this model species at a resolution that enabled individual amino acid visualization. These observations revealed calcium binding only at six specific sites in the LH1 subunit. In contrast, the closely related thermophilic bacterium Thermochromatium tepidum displayed calcium attachment across all 16 LH1 subunits, indicating a calcium binding dependence on the amino acid sequence pattern. These results imply an evolutionary adaptation in this species, enabling it to bind trace amounts of calcium in low-calcium environments, thereby improving its thermal stability for photosynthesis. These findings would potentially advance the efficient use of solar energy, and contribute to environmental protection, and highlight the capability of certain species to conduct photosynthesis in freshwater while detoxifying hydrogen sulfide, which is toxic to numerous organisms, into sulfur. This research was partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Numbers JP21am0101118 and JP21am0101116, and JP23ama121004

2023-03-13

·生物谷

Mol Cancer：我国科学家揭示赖氨酸羟化酶1促进肝癌细胞和胰腺癌细胞迁移和转移

癌症转移是导致癌症相关死亡的一个主要原因。在一项新的研究中，来自中国香港城市大学和重庆医科大学第二附属医院的研究人员发现了一种引发肝癌细胞和胰腺癌细胞迁移和转移并且与患者的生存时间缩短有关的蛋白。癌症转移是导致癌症相关死亡的一个主要原因。在一项新的研究中，来自中国香港城市大学和重庆医科大学第二附属医院的研究人员发现了一种引发肝癌细胞和胰腺癌细胞迁移和转移并且与患者的生存时间缩短有关的蛋白。这些研究结果经体外和体内模型验证，并有临床数据支持，有望为癌症治疗提供一种新的潜在靶标。相关研究结果近期发表在Molecular Cancer期刊上，论文标题为“Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network”。论文共同通讯作者、香港城市大学生物医学讲座教授Michael Yang Mengsu博士说，“癌症转移是一个复杂的过程。众所周知，肿瘤和周围组织的硬化程度随着肿瘤的生长而增加，这在多种癌症类型中为肿瘤细胞的迁移和转移创造了有限空间（confined space），即通道状的孔隙轨道。但这种在有限空间中迁移（下称受限迁移）的机制仍不清楚。我们的目标是深入研究癌症转移机制，并确定与之相关的新基因和蛋白。” 作为最常见的肝癌类型，肝细胞癌（HCC）是世界上第二大癌症死因。胰腺导管腺癌（PDAC）是另一种高度侵袭性的癌症，五年生存率不到10%。这两种癌症都具有实体瘤的典型特征，即胞外基质（ECM）沉积过多，含有使癌细胞迁移的有限孔隙或通道状轨道。因此，这些作者选择了这两种不同的癌症类型作为研究对象。开发研究迁移机制的方法这些作者首先收集了分别来自153名和63名患者的HCC和PDAC样本进行分析。这些作者在手术前没有接受化疗或放疗。他们还从美国国家卫生研究院获得了人类肝癌和胰腺癌细胞系。 Yang教授解释说，“主要的挑战是模拟复杂的癌症微环境。但目前缺乏关于细胞在有限环境中迁移的研究模型。因此，我们开发了一系列多维平台以及二维和三维体外和体内模型，以全面研究细胞迁移过程。” 这些平台和模型包括用于研究单个细胞和集体细胞迁移的微流控芯片，以及用于模拟体内环境的三维侵袭试验的不同硬度的水凝胶。他们还利用下一代测序（NGS）和液相色谱-质谱（LC-MS）来确定癌症组织中差异表达的基因和蛋白。 LH1是促进HCC和PDAC细胞受限迁移的一种关键因子基于下一代测序的转录组分析和基于LC-MS的蛋白质组分析，这些作者确定了一种名为赖氨酸羟化酶1（lysyl hydroxylase 1, LH1）的蛋白是HCC组织中最明显过表达的蛋白之一。他们开发的微流控芯片和三维侵袭模型展示了LH1在多维度上促进受限迁移的能力，包括HCC和PDAC细胞的迁移速度和侵袭能力。这些作用可以通过敲除LH1的表达而被抑制。 LH1高表达与HCC和PDAC患者预后不良相关。图片来自Molecular Cancer, 2023, doi:10.1186/s12943-023-01727-9。他们还证实LH1可以结合并稳定Septin2（SEPT2）以增强肌动蛋白网络的形成；作为一种蛋白，SEPT2在为细胞的高机械迁移需求做准备时起着至关重要的作用。肌动蛋白网络是细胞骨架中最有活力的元素，分布在整个细胞质中，并控制着细胞的力学和运动。因此，增强肌动蛋白网络的形成可以促进HCC和PDAC细胞的受限迁移和转移。 LH1高表达水平导致癌症患者预后不良这些作者还分析了LH1与HCC和PDAC患者的预后（即疾病的发展和复发的机会）之间的相关性。临床样本显示LH1表达较高伴随着预后不佳的患者的生存率只有LH1低表达的患者的一半。此外，LH1高表达的HCC和PDAC患者从确诊到死亡的总生存时间较短，分别为39和17个月，而LH1水平较低的患者则为86和22个月。另外，LH1高表达的HCC和PDAC患者从初次治疗到疾病复发的无病生存时间分别为11.5和14个月，而LH1水平较低的患者为41和19个月。 Yang教授说，“我们开发的平台和方法为研究癌细胞的受限迁移提供了一种独特的方法。我们证实了LH1通过稳定SEPT2促进癌细胞的受限迁移和转移，并且高水平的LH1与HCC和PDAC患者的不良预后有关。这些发现有望为癌症诊断和药物开发提供一种潜在的新靶标。”（生物谷 Bioon.com）参考资料： Zihan Yang et al. Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network. Molecular Cancer, 2023, doi:10.1186/s12943-023-01727-9.