Last update 01 Nov 2024

PLD4

Last update 01 Nov 2024

Basic Info

Synonyms

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

+ [5]

Introduction

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.

Drugs associated with PLD4

SBI-3150

Target

PLD4

Mechanism

PLD4 inhibitors

Active Org.

Asahi Kasei Pharma Corp.

Originator Org.

SBI Biotech Co., Ltd.

Active Indication

Autoimmune Diseases

Inactive Indication

Systemic Lupus Erythematosus

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PLD4

JPRN-jRCT2071230085 / RecruitingPhase 1IIT

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

Start Date08 Nov 2023

Sponsor / Collaborator-

100 Clinical Results associated with PLD4

100 Translational Medicine associated with PLD4

0 Patents (Medical) associated with PLD4

Literatures (Medical) associated with PLD4

01 Oct 2024·Cell

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

Article

Author: 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.

01 Sep 2024·mLife

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

Article

Author: 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.

01 Jul 2024·Immunity

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

Article

Author: 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.

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