αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells.
αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells.
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DOI：
10.1038/ncomms10917
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发表时间：
2016-03-11
影响因子：
16.6
通讯作者：
Lacy-Hulbert A
中科院分区：
文献类型：
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作者：
Acharya M;Sokolovska A;Tam JM;Conway KL;Stefani C;Raso F;Mukhopadhyay S;Feliu M;Paul E;Savill J;Hynes RO;Xavier RJ;Vyas JM;Stuart LM;Lacy-Hulbert A
整合素信号触发细胞骨架重排，包括整合素和其他膜蛋白的内吞和胞吐。除了回收整合素，这种运输还可以调节细胞内信号传导途径。在这里，我们描述了αv整合素在调节Toll样受体（TLR）信号转导通过调节细胞内运输的作用。我们发现，αv或β3的缺失导致体外B细胞对TLR刺激的反应增加，α v条件性敲除小鼠对TLR配体相关抗原的抗体反应升高。αv通过促进自噬组分LC 3（微管相关蛋白1轻链3）募集至含TLR的内体来调节TLR信号传导，这对于从NF-κB向IRF信号传导的进展以及最终运输至信号传导终止的溶酶体至关重要。LC 3募集的破坏导致NF-κB信号传导延长和B细胞增殖和抗体产生增加。这项工作确定了αv和自噬组分LC 3和atg 5在调节TLR信号传导和B细胞免疫中的先前未被认识的作用。 整合素可以调节抗原特异性和先天性免疫受体信号传导，从而影响免疫细胞功能。在这里，作者表明α v β 3整联蛋白通过调节其运输来控制Toll样受体（TLR）信号传导，以限制TLR介导的B细胞增殖和抗体产生。
Integrin signalling triggers cytoskeletal rearrangements, including endocytosis and exocytosis of integrins and other membrane proteins. In addition to recycling integrins, this trafficking can also regulate intracellular signalling pathways. Here we describe a role for αv integrins in regulating Toll-like receptor (TLR) signalling by modulating intracellular trafficking. We show that deletion of αv or β3 causes increased B-cell responses to TLR stimulation in vitro, and αv-conditional knockout mice have elevated antibody responses to TLR-ligand-associated antigens. αv regulates TLR signalling by promoting recruitment of the autophagy component LC3 (microtubule-associated proteins 1 light chain 3) to TLR-containing endosomes, which is essential for progression from NF-κB to IRF signalling, and ultimately for traffic to lysosomes where signalling is terminated. Disruption of LC3 recruitment leads to prolonged NF-κB signalling and increased B-cell proliferation and antibody production. This work identifies a previously unrecognized role for αv and the autophagy components LC3 and atg5 in regulating TLR signalling and B-cell immunity. Integrins can regulate antigen-specific and innate immune receptor signalling, thereby affecting immune cell function. Here the authors show that avß3 integrin controls Toll-like receptor (TLR) signalling by regulating its trafficking to limit TLR-mediated B-cell proliferation and antibody production.