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PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing

Leukocyte sensing of microbial genetic material often elicits beneficial proinflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked Phospholipase D3 (PLD3) to Alzheimer’s disease and PLD4 to rheumatoid arthritis and systemic scler...

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Autores principales: Gavin, Amanda L., Huang, Deli, Huber, Christoph, Mårtensson, Annica, Tardif, Virginie, Skog, Patrick D., Blane, Tanya R., Thinnes, Therese C., Osborn, Kent, Chong, Hayley S., Kargaran, Farnaz, Kimm, Phoebe, Zeitjian, Armen, Sielski, Rachel L., Briggs, Megan, Schulz, Sebastian R., Zarpellon, Alessandro, Cravatt, Benjamin, Pang, Ee Shan, Teijaro, John, de la Torre, Juan Carlos, O’Keeffe, Meredith, Hochrein, Hubertus, Damme, Markus, Teyton, Luc, Lawson, Brian R., Nemazee, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105523/
https://www.ncbi.nlm.nih.gov/pubmed/30111894
http://dx.doi.org/10.1038/s41590-018-0179-y
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author Gavin, Amanda L.
Huang, Deli
Huber, Christoph
Mårtensson, Annica
Tardif, Virginie
Skog, Patrick D.
Blane, Tanya R.
Thinnes, Therese C.
Osborn, Kent
Chong, Hayley S.
Kargaran, Farnaz
Kimm, Phoebe
Zeitjian, Armen
Sielski, Rachel L.
Briggs, Megan
Schulz, Sebastian R.
Zarpellon, Alessandro
Cravatt, Benjamin
Pang, Ee Shan
Teijaro, John
de la Torre, Juan Carlos
O’Keeffe, Meredith
Hochrein, Hubertus
Damme, Markus
Teyton, Luc
Lawson, Brian R.
Nemazee, David
author_facet Gavin, Amanda L.
Huang, Deli
Huber, Christoph
Mårtensson, Annica
Tardif, Virginie
Skog, Patrick D.
Blane, Tanya R.
Thinnes, Therese C.
Osborn, Kent
Chong, Hayley S.
Kargaran, Farnaz
Kimm, Phoebe
Zeitjian, Armen
Sielski, Rachel L.
Briggs, Megan
Schulz, Sebastian R.
Zarpellon, Alessandro
Cravatt, Benjamin
Pang, Ee Shan
Teijaro, John
de la Torre, Juan Carlos
O’Keeffe, Meredith
Hochrein, Hubertus
Damme, Markus
Teyton, Luc
Lawson, Brian R.
Nemazee, David
author_sort Gavin, Amanda L.
collection PubMed
description Leukocyte sensing of microbial genetic material often elicits beneficial proinflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked Phospholipase D3 (PLD3) to Alzheimer’s disease and PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins whose functions are obscure. PLD4-deficient mice were found to have an inflammatory disease, marked by elevated interferon-γ (IFN-γ) and splenomegaly. These phenotypes were traced to an altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA (ssDNA) sensor Toll-like receptor 9 (TLR9). Macrophages from PLD3-deficient mice also had exaggerated TLR9 responses. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5′ exonucleases, likely identical to spleen phosphodiesterase, that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 developed lethal early life liver inflammation indicating that both enzymes are required to regulate inflammatory cytokine responses by degradation of nucleic acids.
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spelling pubmed-61055232019-02-13 PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing Gavin, Amanda L. Huang, Deli Huber, Christoph Mårtensson, Annica Tardif, Virginie Skog, Patrick D. Blane, Tanya R. Thinnes, Therese C. Osborn, Kent Chong, Hayley S. Kargaran, Farnaz Kimm, Phoebe Zeitjian, Armen Sielski, Rachel L. Briggs, Megan Schulz, Sebastian R. Zarpellon, Alessandro Cravatt, Benjamin Pang, Ee Shan Teijaro, John de la Torre, Juan Carlos O’Keeffe, Meredith Hochrein, Hubertus Damme, Markus Teyton, Luc Lawson, Brian R. Nemazee, David Nat Immunol Article Leukocyte sensing of microbial genetic material often elicits beneficial proinflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked Phospholipase D3 (PLD3) to Alzheimer’s disease and PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins whose functions are obscure. PLD4-deficient mice were found to have an inflammatory disease, marked by elevated interferon-γ (IFN-γ) and splenomegaly. These phenotypes were traced to an altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA (ssDNA) sensor Toll-like receptor 9 (TLR9). Macrophages from PLD3-deficient mice also had exaggerated TLR9 responses. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5′ exonucleases, likely identical to spleen phosphodiesterase, that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 developed lethal early life liver inflammation indicating that both enzymes are required to regulate inflammatory cytokine responses by degradation of nucleic acids. 2018-08-13 2018-09 /pmc/articles/PMC6105523/ /pubmed/30111894 http://dx.doi.org/10.1038/s41590-018-0179-y Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Gavin, Amanda L.
Huang, Deli
Huber, Christoph
Mårtensson, Annica
Tardif, Virginie
Skog, Patrick D.
Blane, Tanya R.
Thinnes, Therese C.
Osborn, Kent
Chong, Hayley S.
Kargaran, Farnaz
Kimm, Phoebe
Zeitjian, Armen
Sielski, Rachel L.
Briggs, Megan
Schulz, Sebastian R.
Zarpellon, Alessandro
Cravatt, Benjamin
Pang, Ee Shan
Teijaro, John
de la Torre, Juan Carlos
O’Keeffe, Meredith
Hochrein, Hubertus
Damme, Markus
Teyton, Luc
Lawson, Brian R.
Nemazee, David
PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
title PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
title_full PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
title_fullStr PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
title_full_unstemmed PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
title_short PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
title_sort pld3 and pld4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105523/
https://www.ncbi.nlm.nih.gov/pubmed/30111894
http://dx.doi.org/10.1038/s41590-018-0179-y
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