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NLRX1 促进 LPS 诱导的 LC3 相关噬作用，从而促进巨噬细胞细胞因子的产生。

NLRX1 Facilitates -Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages.

机构信息

Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.

Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.

出版信息

Front Immunol. 2018 Dec 3;9:2761. doi: 10.3389/fimmu.2018.02761. eCollection 2018.

DOI:10.3389/fimmu.2018.02761
PMID:30559741
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6286976/
Abstract

LC3-associated phagocytosis (LAP) is an emerging non-canonical autophagy process that bridges signaling from pattern-recognition receptors (PRRs) to autophagic machinery. LAP formation results in incorporation of lipidated LC3 into phagosomal membrane (termed LAPosome). Increasing evidence reveals that LAP functions as an innate defense mechanism against fungal pathogens. However, the molecular mechanism involved and the consequence of LAP in regulating anti-fungal immune response remain largely unexplored. Here we show that is taken into LAPosome upon phagocytosis by macrophages. Interaction of with Dectin-1 activates Syk and triggers subsequent NADPH oxidase-mediated reactive oxygen species (ROS) response that is involved in LAP induction. Inhibiting LAP induction by silencing LC3α/β or treatment with ROS inhibitor impairs the activation of MAPKs-AP-1 pathway, thereby reduces macrophage proinflammatory cytokine response to . Additionally, we unravel the importance of NLRX1 in fungus-induced LAP. NLRX1 facilitates LAP by interacting with TUFM which associates with autophagic proteins ATG5-ATG12 for LAPosome formation. Macrophages from mice or TUFM-silenced cells exhibit reduced LAP induction and LAP-mediated MAPKs-AP-1 activation for cytokine response to . Furthermore, inhibiting ROS production in macrophages almost completely abolishes -induced LC3 conversion, indicating that both Dectin-1/Syk/ROS-dependent pathway and NLRX1-TUFM complex-dependent pathway collaboratively contribute to LAP induction. Our findings reveal new pathways underlying LAP induction by for macrophage cytokine response.

摘要

LC3 相关的噬作用 (LAP) 是一种新兴的非经典自噬过程，它将模式识别受体 (PRRs) 的信号传递到自噬机制。LAP 的形成导致脂化 LC3 掺入吞噬体膜（称为 LAPosome）。越来越多的证据表明，LAP 作为一种针对真菌病原体的先天防御机制发挥作用。然而，LAP 在调节抗真菌免疫反应中的作用机制和后果在很大程度上仍未得到探索。在这里，我们表明在巨噬细胞吞噬后被纳入 LAPosome。 与 Dectin-1 的相互作用激活了 Syk，并引发随后的 NADPH 氧化酶介导的活性氧 (ROS) 反应，该反应参与 LAP 的诱导。通过沉默 LC3α/β 或用 ROS 抑制剂抑制 LAP 的诱导会损害 MAPKs-AP-1 途径的激活，从而减少巨噬细胞对 的促炎细胞因子反应。此外，我们揭示了 NLRX1 在真菌诱导的 LAP 中的重要性。NLRX1 通过与 TUFM 相互作用促进 LAP，TUFM 与自噬蛋白 ATG5-ATG12 相关，用于 LAPosome 的形成。来自 小鼠或 TUFM 沉默细胞的巨噬细胞显示出减少的 LAP 诱导和 LAP 介导的 MAPKs-AP-1 激活，以响应细胞因子。此外，在 巨噬细胞中抑制 ROS 的产生几乎完全消除了 -诱导的 LC3 转化，表明 Dectin-1/Syk/ROS 依赖性途径和 NLRX1-TUFM 复合物依赖性途径协同促进 LAP 的诱导。我们的研究结果揭示了 诱导巨噬细胞细胞因子反应的 LAP 诱导的新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/91eb00545bf1/fimmu-09-02761-g0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/ba511785123b/fimmu-09-02761-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/f1eeb4f60e68/fimmu-09-02761-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/742f6dbca3aa/fimmu-09-02761-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/4f17b622ac24/fimmu-09-02761-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/2562f43b47ce/fimmu-09-02761-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/3095ebd7aad3/fimmu-09-02761-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/df432d093923/fimmu-09-02761-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/4608a64f8d1c/fimmu-09-02761-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/a7216514860c/fimmu-09-02761-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/91eb00545bf1/fimmu-09-02761-g0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/ba511785123b/fimmu-09-02761-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/f1eeb4f60e68/fimmu-09-02761-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/742f6dbca3aa/fimmu-09-02761-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/4f17b622ac24/fimmu-09-02761-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/2562f43b47ce/fimmu-09-02761-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/3095ebd7aad3/fimmu-09-02761-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/df432d093923/fimmu-09-02761-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/4608a64f8d1c/fimmu-09-02761-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/a7216514860c/fimmu-09-02761-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16c1/6286976/91eb00545bf1/fimmu-09-02761-g0010.jpg

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