title: The primary cilium influences interleukin-1β-induced NFκB signalling by regulating IKK activity.
abstract: 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.
authors.affiliation: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, United Kingdom. Electronic address: a.wann@qmul.ac.uk.
authors.forename: A K T
authors.initials: AK
authors.lastname: Wann
authors.affiliation: 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. Electronic address: j.p.chapple@qmul.ac.uk.
authors.forename: J P
authors.initials: JP
authors.lastname: Chapple
authors.affiliation: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, United Kingdom. Electronic address: M.M.Knight@qmul.ac.uk.
authors.forename: M M
authors.initials: MM
authors.lastname: Knight
mesh_terms: D000818:Animals; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D055551:HSP27 Heat-Shock Proteins; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: Chondrocyte; IKK; Inflammation; Interleukin-1; NFκB signalling; Primary cilium
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