PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.
PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.
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DOI：
10.1038/s41590-018-0179-y
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发表时间：
2018-09
影响因子：
30.5
通讯作者：
Nemazee D
中科院分区：
文献类型：
--
作者：
Gavin AL;Huang D;Huber C;Mårtensson A;Tardif V;Skog PD;Blane TR;Thinnes TC;Osborn K;Chong HS;Kargaran F;Kimm P;Zeitjian A;Sielski RL;Briggs M;Schulz SR;Zarpellon A;Cravatt B;Pang ES;Teijaro J;de la Torre JC;O'Keeffe M;Hochrein H;Damme M;Teyton L;Lawson BR;Nemazee D
白细胞对微生物遗传物质的敏感性通常会激发有益的促炎细胞因子，但失调的反应可导致严重的发病机制。全基因组关联研究已经将磷脂酶D3（PLD 3）与阿尔茨海默病联系起来，将PLD 4与类风湿性关节炎和系统性硬化症联系起来。PLD 3和PLD 4是内溶酶体蛋白，其功能尚不清楚。发现PLD 4缺陷型小鼠患有炎症性疾病，其特征为干扰素-γ（IFN-γ）升高和脾肿大。这些表型被追踪到PLD 4缺陷树突状细胞对单链DNA（ssDNA）传感器Toll样受体9（TLR 9）的配体的改变的响应性。来自PLD 3缺陷小鼠的巨噬细胞也具有夸大的TLR 9应答。虽然PLD 4和PLD 3被认为是磷脂酶，但我们发现它们是5′核酸外切酶，可能与脾磷酸二酯酶相同，可分解TLR 9配体。缺乏PLD 3和PLD 4的小鼠出现致命的早期肝脏炎症，这表明这两种酶都是通过核酸降解来调节炎症细胞因子反应所必需的。
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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影响因子：
56.9
作者：
Kawane, K;Fukuyama, H;Nagata, S
通讯作者：
Nagata, S
DOI：
10.1186/1745-7580-4-5
发表时间：
2008-04-29
期刊：
Immunome research
影响因子：
--
作者：
Lattin JE;Schroder K;Su AI;Walker JR;Zhang J;Wiltshire T;Saijo K;Glass CK;Hume DA;Kellie S;Sweet MJ
通讯作者：
Sweet MJ
DOI：
10.1111/j.1432-1033.1969.tb00511.x
发表时间：
1969-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
IPATA, PL;FELICIOL.RA
通讯作者：
FELICIOL.RA
影响因子：
5.6
作者：
Chen, Jey-Hsin;Fleming, Mark D.;Perez-Atayde, Antonio R.
通讯作者：
Perez-Atayde, Antonio R.
影响因子：
7.7
作者：
Luecke, Stefanie;Holleufer, Andreas;Paludan, Soren R.
通讯作者：
Paludan, Soren R.