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.

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

“…A number of candidate pathways lie upstream in the regulation of aggrecanase activity. The NF-κB pathway is upstream of aggrecanase transcription (8), and its activity is regulated by IFT88, but only in response to cytokine (38). Recently, in chondrocytes, the JNK2 pathway has been linked to OA protease activity (9); however, we find that IFT88 ORPK cells do not have constitutive JNK2 activity.…”

“…Whereas Hh signaling is activated in OA (35), the activation of the pathway alone does not drive cartilage catabolism (36). In chondrocytes, ciliary IFT is also important for the cellular response to pathophysiologically relevant stimuli, such as mechanics, inflammatory cytokines, and osmotic flux (25,(37)(38)(39)(40). Here, we experimentally examined whether the ciliome, specifically IFT88, directly regulates matrix catabolism independent of transducing pathophysiologic stimuli.…”

Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

“…Minashima et al (5) report that LiCl inhibits NF‐κB signaling in response to IL‐1 treatment. Previously we have reported a role for the cilium in NF‐κB signaling such that, in the absence of cilia, NF‐κB signaling is both delayed and attenuated, a consequence of which is that chondrocytes are unable to up regulate nitric oxide and prostaglandin E 2 production in response to IL‐1 (62, 69). Therefore, an intriguing possibility is that LiCl might also be influencing inflammatory signaling through the modulation of cilia length; however, this remains to be investigated.…”

Dynein and intraflagellar transport

“…Overexpression and knockdown analysis of WDR34 suggested that WDR34 is a TAK1-associated inhibitor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. This and later findings led to the recent proposal that the cilium is a locality for regulation of the molecular events defining NFκB signalling events, tuning signalling as appropriate (Wann et al, 2014). Knockdown of the zebrafish WDR34 homologue confirmed the involvement of this protein in ciliary assembly (Krock et al, 2009).…”