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Intraflagellar transport (IFT) is required for proper function of cilia, although many of the mechanistic details underlying this process are obscure. Two studies in this issue of Developmental Cell illuminate key functions of one IFT protein, IFT27, and offer clues into how IFT cargo is selected and transported.
Intraflagellar transport (IFT), the regulated movement of cargo along the ciliary axoneme, is critical for ciliary biogenesis and function (
). Complete disruption of IFT leads to either failure of ciliogenesis or severe distortion of ciliary architecture, both of which are incompatible with life, while hypomorphic mutations give rise to severe multi-organ pathologies that, in humans, manifest in acute neonatal disorders (
provide molecular insights into the mechanisms underlying IFT cargo selection and hint at regulated interactions between some IFT components and other ciliary complexes to regulate paracrine signaling (
Initial biochemical studies of IFT defined two key particles, IFT-B and IFT-A. IFT-B is composed of 16 core members mounted on kinesin motors and is responsible for cargo transport from the base of the cilium to the tip (anterograde transport). IFT-A, the retrograde core particle, is composed of six core proteins driven by dynein motors (
). The two reports in this issue of Developmental Cell reveal further complexity and suggest that IFT27, historically considered a dedicated anterograde transport protein, may also participate in retrograde transport (
investigated the molecular underpinnings of the ciliopathy phenotypes observed in a new Ift27−/− mouse model, including polydactyly, cardiac malformations, situs inversus, and craniofacial defects. The authors noted that although Ift27−/− mouse embryonic fibroblasts (MEFs) do not display overt structural defects indicative of disrupted IFT, they exhibit attenuated SHH signaling concomitant with the accumulation of SHH components, including the transmembrane receptors patched (PTCH), smoothened (SMO), and the SHH G protein-coupled receptor intermediate GPR161. Moreover, in the absence of IFT27, the authors observed aberrant ciliary localization of multiple BBSome components, as well as BBSome-associated proteins such as ARL6/BBS3 and LZTFL1/BBS17. The authors also found that cells lacking Lztfl1, another causative BBS gene that participates in BBSome-mediated protein trafficking (
utilized ciliated in vitro models coupled with biochemical analyses to examine the interaction of IFT27 with the BBSome. First, the authors found that IFT27 binds to ARL6. ARL6 is a GTPase, like IFT27, and a known effector of the BBSome, required for its targeting to the cilium. In addition, cells with both suppressed Ift27 expression and Ift27−/− MEFS were found to accumulate BBSome components and ARL6 in their cilia. Finally, and consistent with a previously suggested role for the BBSome in sorting SHH signaling components entering the cilium upon pathway activation (
), lack of IFT27 resulted in the ciliary accumulation of transmembrane receptors PTCH, SMO, and GPR161, presumably because these proteins fail to exit. The authors propose that, in addition to a canonical role in anterograde transport in cooperation with the IFT-B complex, IFT27 can dissociate from IFT-B to bind and activate ARL6, a process necessary for targeted removal of SHH components from the cilium.
Together, these two studies hint at a previously underappreciated interaction between two of the most highly characterized ciliary modules, the IFT machinery, and the BBSome, and provide important new clues about trafficking of signaling moieties from the ciliary compartment to the cell (Figure 1). However, the biological reality is likely to be even more complex. For instance, suppression of ift27 in Chlamydomonas or Trypanosoma caused a reduction of IFT-A and IFT-B amounts (
, suggesting that either this IFT27 function has been lost in higher vertebrates or that it might only exist in cell types not interrogated in the current studies. In addition, the defects in SHH component trafficking raises the question of whether IFT27 is dedicated to responding to SHH activation or whether this method of removing proteins from the cilium might also apply to other signaling molecules. All of these questions must be placed in the broader context of ciliary function in different tissues and developmental time points.
Finally, it will be important to place these findings in the context of human genetic disease. Ift27−/− mice exhibit severe ciliopathy hallmarks and cannot survive past birth (
). These discordant observations may be driven by allelic differences or by non-identical functions of IFT27 in mice and humans. Ultimately, the synthesis of data from diverse cell types, organisms, and developmental and homeostatic contexts will be required to gain a deeper appreciation of the diverse roles of IFT proteins, their accessory subunits, their cargo, and, more broadly, the complexity that underpins ciliary function.
The Arf-like GTPase ARL6 triggers BBSome coat assembly and cargo entry into cilia. Now, Liew et al. find that the Rab-like GTPase IFT27 disengages from anterograde IFT complexes to bind and activate nucleotide-empty ARL6 and thereby promote the exit of the BBSome and its associated cargoes from cilia.
In vertebrates, hedgehog signaling is organized in the cilium, and ciliary defects affect signaling. Eguether et al. find that intraflagellar transport proteins IFT25 and IFT27 are not required for ciliary assembly but couple ciliary trafficking of hedgehog signaling components to the IFT particle through the BBSome and BBSome regulator Lztfl1.