Wann A K T, Chapple J P, Knight M M
Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, United Kingdom.
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane science building, Charterhouse square, London EC1M 6BQ, United Kingdom.
Cell Signal. 2014 Aug;26(8):1735-42. doi: 10.1016/j.cellsig.2014.04.004. Epub 2014 Apr 12.
The primary cilium is an organelle acting as a master regulator of cellular signalling. We have previously shown that disruption of primary cilia assembly, through targeting intraflagellar transport, is associated with muted nitric oxide and prostaglandin responses to the inflammatory cytokine interleukin-1β (IL-1β). Here, we show that loss of the primary cilium disrupts specific molecular signalling events in cytosolic NFκB signalling. The induction of cyclooxygenase 2 (COX2) and inducible nitrous oxide synthase (iNOS) protein is abolished. Cells unable to assemble cilia exhibit unaffected activation of IκB kinase (IKK), but delayed and reduced degradation of IκB, due to diminished phosphorylation of inhibitor of kappa B (IκB) by IKK. This results in both delayed and reduced NFκB p65 nuclear translocation and nuclear transcript binding. We also demonstrate that heat shock protein 27 (hsp27), an established regulator of IKK, is localized to the ciliary axoneme and cellular levels are dramatically disrupted with loss of the primary cilium. These results suggest that the primary cilia compartment exerts influence over NFκB signalling. We propose that the cilium is a locality for regulation of the molecular events defining NFκB signalling events, tuning signalling as appropriate.
初级纤毛是一种作为细胞信号传导主要调节因子的细胞器。我们之前已经表明，通过靶向鞭毛内运输来破坏初级纤毛组装，与对炎性细胞因子白细胞介素-1β（IL-1β）的一氧化氮和前列腺素反应减弱有关。在此，我们表明初级纤毛的缺失会破坏细胞质核因子κB（NFκB）信号传导中的特定分子信号事件。环氧化酶2（COX2）和诱导型一氧化氮合酶（iNOS）蛋白的诱导被消除。无法组装纤毛的细胞显示IκB激酶（IKK）的激活未受影响，但由于IKK对κB抑制因子（IκB）的磷酸化减少，IκB的降解延迟且减少。这导致NFκB p65核转位和核转录结合均延迟且减少。我们还证明，热休克蛋白27（hsp27）作为一种既定的IKK调节因子，定位于纤毛轴丝，并且随着初级纤毛的缺失，细胞水平会受到显著破坏。这些结果表明初级纤毛区室对NFκB信号传导有影响。我们提出，纤毛是调节定义NFκB信号事件的分子事件的场所，可根据需要调整信号传导。
