P. gingivalis-Induced TLR2 Interactome Analysis Reveals Association with PARP9.

Journal of dental research Pub Date : 2024-03-01 Epub Date: 2024-02-12 DOI:10.1177/00220345231222181
K Pandi, S Angabo, H Makkawi, H Benyamini, S Elgavish, G Nussbaum
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Abstract

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium strongly associated with periodontal disease. Toll-like receptor 2 (TLR2) is indispensable for the host response to P. gingivalis, but P. gingivalis escapes from immune clearance via TLR2-dependent activation of phosphoinositide-3-kinase (PI3K). To probe the TLR2-dependent escape pathway of P. gingivalis, we analyzed the TLR2 interactome induced following P. gingivalis infection or activation by a synthetic lipopeptide TLR2/1 agonist on human macrophages overexpressing TLR2. Interacting proteins were stabilized by cross-linking and then immunoprecipitated and analyzed by mass spectrometry. In total, 792 proteins were recovered and network analysis enabled mapping of the TLR2 interactome at baseline and in response to infection. The P. gingivalis infection-induced TLR2 interactome included the poly (ADP-ribose) polymerase family member mono-ADP-ribosyltransferase protein 9 (PARP9) and additional members of the PARP9 complex (DTX3L and NMI). PARP9 and its complex members are highly upregulated in macrophages exposed to P. gingivalis or to the synthetic TLR2/1 ligand Pam3Cys-Ser-(Lys)4 (PAM). Consistent with its known role in virally induced interferon production, PARP9 knockdown blocked type I interferon (IFN-I) production in response to P. gingivalis and reduced inflammatory cytokine production. We found that P. gingivalis drives signal transducer and activation of transcription (STAT) 1 (S727) phosphorylation through TLR2-PARP9, explaining PARP9's role in the induction of IFN-I downstream of TLR2. Furthermore, PARP9 knockdown reduced PI3K activation by P. gingivalis, leading to improved macrophage bactericidal activity. In summary, PARP9 is a novel TLR2 interacting partner that enables IFN-I induction and P. gingivalis immune escape in macrophages downstream of TLR2 sensing.

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牙龈脓疱病诱导的 TLR2 相互作用组分析显示与 PARP9 有关。
牙龈卟啉单胞菌是一种与牙周病密切相关的革兰氏阴性厌氧菌。Toll样受体2(TLR2)是宿主对牙龈卟啉单胞菌做出反应所不可或缺的,但牙龈卟啉单胞菌通过TLR2依赖性激活磷酸肌醇-3-激酶(PI3K)逃避免疫清除。为了探究牙龈脓毒性噬菌体依赖 TLR2 的逃逸途径,我们分析了牙龈脓毒性噬菌体感染或在过表达 TLR2 的人巨噬细胞上被合成脂肽 TLR2/1 激动剂激活后诱导的 TLR2 相互作用组。通过交联稳定相互作用蛋白,然后进行免疫沉淀和质谱分析。共回收了 792 个蛋白质,并通过网络分析绘制出了基线和感染时 TLR2 相互作用组的图谱。牙龈球菌感染诱导的 TLR2 相互作用组包括聚(ADP-核糖)聚合酶家族成员单-ADP-核糖基转移酶蛋白 9(PARP9)和 PARP9 复合物的其他成员(DTX3L 和 NMI)。PARP9 及其复合体成员在暴露于牙龈脓疱病菌或合成 TLR2/1 配体 Pam3Cys-Ser-(Lys)4 (PAM) 的巨噬细胞中高度上调。与已知的 PARP9 在病毒诱导的干扰素产生中的作用相一致,PARP9 基因敲除会阻止 I 型干扰素(IFN-I)在牙龈脓疱病中的产生,并减少炎性细胞因子的产生。我们发现牙龈脓疱疮通过 TLR2-PARP9 驱动信号转导和激活转录(STAT)1 (S727) 磷酸化,这解释了 PARP9 在 TLR2 下游诱导 IFN-I 中的作用。此外,PARP9 的敲除减少了牙龈脓毒性杆菌对 PI3K 的激活,从而提高了巨噬细胞的杀菌活性。总之,PARP9 是一种新型的 TLR2 相互作用伙伴,它能在 TLR2 传感下游诱导 IFN-I 并使牙龈脓疱噬菌体免疫逃逸。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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