Acharya Mridu, Sokolovska Anna, Tam Jenny M, Conway Kara L, Stefani Caroline, Raso Fiona, Mukhopadhyay Subhankar, Feliu Marianela, Paul Elahna, Savill John, Hynes Richard O, Xavier Ramnik J, Vyas Jatin M, Stuart Lynda M, Lacy-Hulbert Adam
Immunology Program, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, Washington 98101, USA.
Laboratory of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
Nat Commun. 2016 Mar 11;7:10917. doi: 10.1038/ncomms10917.
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.
整合素信号传导触发细胞骨架重排，包括整合素及其他膜蛋白的内吞作用和胞吐作用。除了使整合素循环利用外，这种运输还可调节细胞内信号通路。在此，我们描述了αv整合素在通过调节细胞内运输来调控Toll样受体（TLR）信号传导中的作用。我们发现，敲除αv或β3会导致体外B细胞对TLR刺激的反应增强，且αv条件性敲除小鼠对TLR配体相关抗原的抗体反应升高。αv通过促进自噬成分LC3（微管相关蛋白1轻链3）募集到含TLR的内体来调节TLR信号传导，这对于从NF-κB信号传导转变为IRF信号传导至关重要，最终对于信号传导终止的溶酶体运输也至关重要。LC3募集的破坏会导致NF-κB信号传导延长，并增加B细胞增殖和抗体产生。这项工作确定了αv以及自噬成分LC3和自噬相关基因5（atg5）在调节TLR信号传导和B细胞免疫方面以前未被认识的作用。
