An endosomal LAPF is required for macrophage endocytosis and elimination of bacteria
An endosomal LAPF is required for macrophage endocytosis and elimination of bacteria
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巨噬细胞内吞作用和消除细菌需要内体 LAPF
DOI：
10.1073/pnas.1903896116
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发表时间：
2019-06-25
影响因子：
11.1
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Li, Tianliang;Qin, Kewei;Cao, Xuetao
宿主固有免疫细胞，如巨噬细胞，可以内吞入侵的病原体并诱导炎症性固有反应以对抗感染。在这项研究中，我们表明，Cav 1相互作用的蛋白，LAPF，促进细菌的内吞作用和促炎细胞因子的产生诱导Src-LAPF-小窝蛋白复合物的形成，在响应先天刺激。我们的研究结果揭示了宿主通过增加巨噬细胞内吞作用和诱导先天性反应来抵抗细菌感染的防御策略。我们建议，药理学激活LAPF和Src可能被应用于控制细菌感染。巨噬细胞可以通过筏/小窝和/或网格蛋白依赖的内吞作用内化入侵的病原体，并引发针对感染的免疫应答。然而，巨噬细胞内吞作用的分子机制仍然难以捉摸。在这里，我们报告，LAPF（溶酶体相关的和溶酶体诱导蛋白含有PH和FYVE结构域）是所需的小窝介导的内吞作用。lapf缺陷的巨噬细胞内吞和消除细菌的能力受损。巨噬细胞特异性Lapf缺陷小鼠对大肠杆菌（E. coli）更敏感。大肠杆菌）感染。此外，Lapf缺陷损害TLR 4内吞作用，导致TLR触发的促炎细胞因子的产生减弱。LAPF定位于早期内体并与小窝蛋白-1相互作用。LAPF被酪氨酸激酶Src磷酸化是LAPF-Src-Caveolin复合物形成和细菌内吞作用和消除所必需的。总的来说，我们的工作表明，LAPF是细菌的内吞作用和诱导炎症反应的关键，这表明LAPF和Src可能是控制传染病的潜在目标。
Significance Host innate immune cells, such as macrophages, can endocytose the invading pathogens and induce inflammatory innate responses to fight infection. In this study, we show that a Cav1-interacting protein, LAPF, promotes the endocytosis of bacteria and production of proinflammatory cytokines by inducing Src-LAPF-Caveolin complex formation in response to innate stimuli. Our results reveal a host defense strategy against bacterial infection by increasing macrophage endocytosis and induction of innate response. We propose that pharmacological activation of LAPF and Src could potentially be applied to the control of bacterial infections. Macrophages can internalize the invading pathogens by raft/caveolae and/or clathrin-dependent endocytosis and elicit an immune response against infection. However, the molecular mechanism for macrophage endocytosis remains elusive. Here we report that LAPF (lysosome-associated and apoptosis-inducing protein containing PH and FYVE domains) is required for caveolae-mediated endocytosis. Lapf-deficient macrophages have impaired capacity to endocytose and eliminate bacteria. Macrophage-specific Lapf-deficient mice are more susceptible to Escherichia coli (E. coli) infection with higher bacterial loads. Moreover, Lapf deficiency impairs TLR4 endocytosis, resulting in attenuated production of TLR-triggered proinflammatory cytokines. LAPF is localized to early endosomes and interacts with caveolin-1. Phosphorylation of LAPF by the tyrosine kinase Src is required for LAPF-Src-Caveolin complex formation and endocytosis and elimination of bacteria. Collectively, our work demonstrates that LAPF is critical for endocytosis of bacteria and induction of inflammatory responses, suggesting that LAPF and Src could be potential targets for the control of infectious diseases.