更新于：2024-11-01

PLD4

更新于：2024-11-01

基本信息

别名

5'-3' exonuclease PLD4、C14orf175、Choline phosphatase 4

+ [5]

简介

5'->3' DNA exonuclease which digests single-stranded DNA (ssDNA). Regulates inflammatory cytokine responses via the degradation of nucleic acids, by reducing the concentration of ssDNA able to stimulate TLR9, a nucleotide-sensing receptor. Involved in phagocytosis of activated microglia.

关联

项与 PLD4 相关的药物

SBI-3150

靶点

PLD4

作用机制

PLD4抑制剂

在研机构

Asahi Kasei Pharma Corp.

原研机构

SBI Biotech Co., Ltd.

在研适应症

自身免疫性疾病

非在研适应症

系统性红斑狼疮

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 PLD4 相关的临床试验

JPRN-jRCT2071230085 / Recruiting临床1期IIT

Phase I Study of AK1910 in Healthy Japanese Subjects, Healthy Caucasian Subjects, Patients with Systemic Lupus Erythematosus (Single Dose and Multiple Dose Study)

开始日期2023-11-08

申办/合作机构-

100 项与 PLD4 相关的临床结果

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100 项与 PLD4 相关的转化医学

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0 项与 PLD4 相关的专利（医药）

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项与 PLD4 相关的文献（医药）

2024-10-01·Cell

PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes

Article

作者: Lopez-Scarim, Joshua ; Ambaw, Yohannes A ; Farese, Robert V. ; Walther, Tobias C ; Ambaw, Yohannes A. ; Farese, Robert V ; Dransfeld, Ulrich E ; Dransfeld, Ulrich E. ; Walther, Tobias C. ; Singh, Shubham

Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer's disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.

2024-09-01·mLife

Catalytically active prokaryotic Argonautes employ phospholipase D family proteins to strengthen immunity against different genetic invaders

Article

作者: Xiang, Hua ; Cheng, Feiyue ; Wu, Aici ; Xu, Jing ; Cao, Xifeng ; Han, Wenyuan ; Li, Zhihua ; Li, Ming ; Wang, Rui ; Liu, Zhenquan ; Yu, Haiying

AbstractProkaryotic Argonautes (pAgos) provide bacteria and archaea with immunity against plasmids and viruses. Catalytically active pAgos utilize short oligonucleotides as guides to directly cleave foreign nucleic acids, while inactive pAgos lacking catalytic residues employ auxiliary effectors, such as nonspecific nucleases, to trigger abortive infection upon detection of foreign nucleic acids. Here, we report a unique group of catalytically active pAgo proteins that frequently associate with a phospholipase D (PLD) family protein. We demonstrate that this particular system employs the catalytic center of the associated PLD protein rather than that of pAgo to restrict plasmid DNA, while interestingly, its immunity against a single‐stranded DNA virus relies on the pAgo catalytic center and is enhanced by the PLD protein. We also find that this system selectively suppresses viral DNA propagation without inducing noticeable abortive infection outcomes. Moreover, the pAgo protein alone enhances gene editing, which is unexpectedly inhibited by the PLD protein. Our data highlight the ability of catalytically active pAgo proteins to employ auxiliary proteins to strengthen the targeted eradication of different genetic invaders and underline the trend of PLD nucleases to participate in host immunity.

2024-07-01·Immunity

Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation

Article

作者: Hornung, Veit ; Lammens, Katja ; Fröhlich, Thomas ; Pinci, Francesca ; Stöckl, Jan ; Piseddu, Ignazio ; Wang, Meiyue ; Bérouti, Marleen ; Carell, Thomas ; Heiss, Matthias ; Hopfner, Karl-Peter ; Bauernfried, Stefan ; Greulich, Wilhelm ; Jung, Christophe ; Hansbauer, Larissa

Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. We found that the endonuclease RNase T2, along with 5' exonucleases PLD3 and PLD4, collaboratively generate the ligands for TLR7. Specifically, RNase T2 generated guanosine 2',3'-cyclic monophosphate-terminated RNA fragments. PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. Loss-of-function studies in cell lines and primary cells confirmed the critical requirement for PLD activity. Biochemical and structural studies showed that PLD enzymes form homodimers with two ligand-binding sites important for activity. Previously identified disease-associated PLD mutants failed to form stable dimers. Together, our data provide a mechanistic basis for the detection of RNA fragments by TLR7.