Figure 6

Proposal for cilia role in the regulation of HIF2α expression/activity. Interleukin-1 (IL-1) stimulates ciliary elongation through Rho-actin dependent modulation of anterograde intraflagellar trafficking (bold arrow, black). This elongation is enhanced in the presence of interleukin-6 (IL-6). Cilia elongation is also dependent on tubulin HDAC activity, most likely HDAC6, and can be blocked by trichostatin A (TSA). IL-1 triggers an initial increase in HIF-2α expression resulting in the sequestration of HIF-2α to the ciliary compartment. The inhibition of prolyl hydroxylases by DMOG, CoCl₂ and hypoxia is also associated with cilia elongation and HIF-2α accumulation, possibly as part of a feedback mechanism such that accumulation of HIF-2a in the cilium drives further cilia elongation. However, HIF-2α is not required for cilia elongation as blockade of HIF transcriptional activity at the nucleus by echinomycin (ECH) has no effect on IL-1-induced elongation. Moreover, the Hsp90 inhibitor geldanamycin (GA) does not influence cilia elongation yet prevents the accumulation of HIF-2α downstream of IL-1. Removal of the cilium, by hypomorphic mutation of IFT88, results in an increase in HIF-2α protein levels suggesting the cilium exerts a negative influence over HIF2α. Consistent with this hypothesis, the IL-1-induced increase in HIF2α is diminished at later time points following ciliary sequestration. Thus we propose that the cilium functions as part of a negative feedback mechanism which influences the levels of HIF2α protein by modulating its proteasomal targeting and ultimate destruction.