IFT27 Links the BBSome to IFT for Maintenance of the Ciliary Signaling Compartment

Eguether, Thibaut; Agustin, Jovenal T. San; Keady, Brian T.; Jonassen, Julie A.; Liang, Yinwen; Francis, Richard; Tobita, Kimimasa; Johnson, Colin A.; Abdelhamed, Zakia; Lo, Cecilia; Pazour, Gregory J.

doi:10.1016/j.devcel.2014.09.011

Cited by 239 publications

(378 citation statements)

References 36 publications

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“…IFT27 was recently shown to play a crucial role in facilitating ciliary exit of the BBSome (Eguether et al, 2014;Ng et al, 2012), and Ift27-deficient mouse embryonic fibroblasts are unable to maintain low levels of SMO in the cilia when the Hh pathway is inactive (Eguether et al, 2014). In this study, we further demonstrated that suppressed Hh signaling in Ift27 −/− primary dermal fibroblasts is also associated with abnormal accumulation of SMO in the cilium.…”

Section: Ift27supporting

confidence: 59%

“…Ift27 −/− and Ift25 −/− mice die shortly after birth due to severe developmental abnormalities in vital organs, such as the heart, spinal cord and lung (Eguether et al, 2014;Keady et al, 2012). These developmental anomalies were linked to disrupted Hh signaling (Eguether et al, 2014;Keady et al, 2012). The extensive phenotypic outcome in Ift27 −/− and Ift25 −/− mice suggests that this subset of IFT proteins might be widely required in the embryonic development of complex organ systems.…”

Section: Discussionmentioning

confidence: 99%

“…These findings demonstrate that the processes required for transducing the Hh signals may be separated from those of ciliogenesis, and that the presence of the ciliary axoneme does not necessarily warrant functionality. Ift27 −/− and Ift25 −/− mice die shortly after birth due to severe developmental abnormalities in vital organs, such as the heart, spinal cord and lung (Eguether et al, 2014;Keady et al, 2012). These developmental anomalies were linked to disrupted Hh signaling (Eguether et al, 2014;Keady et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

Yang

Eguether

et al. 2015

Development

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Hair follicle morphogenesis requires precisely controlled reciprocal communications, including hedgehog (Hh) signaling. Activation of the Hh signaling pathway relies on the primary cilium. Disrupting ciliogenesis results in hair follicle morphogenesis defects due to attenuated Hh signaling; however, the loss of cilia makes it impossible to determine whether hair follicle phenotypes in these cilia mutants are caused by the loss of cilia, disruption of Hh signaling, or a combination of these events. In this study, we characterized the function of Ift27, which encodes a subunit of intraflagellar transport (IFT) complex B. Hair follicle morphogenesis of Ift27-null mice was severely impaired, reminiscent of phenotypes observed in cilia and Hh mutants. Furthermore, the Hh signaling pathway was attenuated in Ift27 mutants, which was in association with abnormal ciliary trafficking of SMO and GLI2, and impaired processing of Gli transcription factors; however, formation of the ciliary axoneme was unaffected. The ciliary localization of IFT25 (HSPB11), the binding partner of IFT27, was disrupted in Ift27 mutant cells, and Ift25-null mice displayed hair follicle phenotypes similar to those of Ift27 mutants. These data suggest that Ift27 and Ift25 operate in a genetically and functionally dependent manner during hair follicle morphogenesis. This study suggests that the molecular trafficking machineries underlying ciliogenesis and Hh signaling can be segregated, thereby providing important insights into new avenues of inhibiting Hh signaling, which might be adopted in the development of targeted therapies for Hh-dependent cancers, such as basal cell carcinoma.

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Section: Ift27supporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

Yang

Eguether

et al. 2015

Development

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“…LZTFL1 mutations were then found in human patients with BBS, rendering it the 17th BBS gene (BBS17) (24,25). More recently, it was shown that Lztfl1 cycles between cilia and the cytoplasm and facilitates removal of the BBSome from cilia (26). In this work, we sought to determine the physiological roles of BBS proteins in photoreceptors and mechanisms of photoreceptor degeneration by using a newly developed Lztfl1 mutant mouse line and quantitative analyses of the OS proteome.…”

Section: Significancementioning

confidence: 99%

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Datta

Allamargot

Hudson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

136

128

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Compartmentalization and polarized protein trafficking are essential for many cellular functions. The photoreceptor outer segment (OS) is a sensory compartment specialized for phototransduction, and it shares many features with primary cilia. As expected, mutations disrupting protein trafficking to cilia often disrupt protein trafficking to the OS and cause photoreceptor degeneration. Bardet-Biedl syndrome (BBS) is one of the ciliopathies associated with defective ciliary trafficking and photoreceptor degeneration. However, precise roles of BBS proteins in photoreceptor cells and the underlying mechanisms of photoreceptor degeneration in BBS are not well understood. Here, we show that accumulation of non-OS proteins in the OS underlies photoreceptor degeneration in BBS. Using a newly developed BBS mouse model [Leucine zipper transcription factor-like 1 (Lztfl1)/Bbs17 mutant], isolated OSs, and quantitative proteomics, we determined 138 proteins that are enriched more than threefold in BBS mutant OS. In contrast, only eight proteins showed a more than threefold reduction. We found striking accumulation of Stx3 and Stxbp1/Munc18-1 and loss of polarized localization of Prom1 within the Lztfl1 and Bbs1 mutant OS. Ultrastructural analysis revealed that large vesicles are formed in the BBS OS, disrupting the lamellar structure of the OS. Our findings suggest that accumulation (and consequent sequestration) of non-OS proteins in the OS is likely the primary cause of photoreceptor degeneration in BBS. Our data also suggest that a major function of BBS proteins in photoreceptors is to transport proteins from the OS to the cell body or to prevent entry of non-OS proteins into the OS.photoreceptor degeneration | trafficking | primary cilia | outer segment | retinitis pigmentosa

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“…This could be important given that trypanosomes swim with the flagellum forward and use the flagellum to attach to the epithelium of the salivary glands during infection in the tsetse fly (Tetley and Vickerman, 1985). Signalling molecules could also be concentrated depending on IFT (Eguether et al, 2014).…”

Section: Ift and The Maintenance Of Flagellar Componentsmentioning

confidence: 99%

Intraflagellar transport is required for the maintenance of the trypanosome flagellum composition but not its length

Fort

Bonnefoy

Kohl

et al. 2016

Journal of Cell Science

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Intraflagellar transport (IFT) is required for construction of most cilia and flagella. Here, we used electron microscopy, immunofluorescence and live video microscopy to show that IFT is absent or arrested in the mature flagellum of Trypanosoma brucei upon RNA interference (RNAi)-mediated knockdown of IFT88 and IFT140, respectively. Flagella assembled prior to RNAi did not shorten, showing that IFT is not essential for the maintenance of flagella length. Although the ultrastructure of the axoneme was not visibly affected, flagellar beating was strongly reduced and the distribution of several flagellar components was drastically modified. The R subunit of the protein kinase A was no longer concentrated in the flagellum but was largely found in the cell body whereas the kinesin 9B motor was accumulating at the distal tip of the flagellum. In contrast, the distal tip protein FLAM8 was dispersed along the flagellum. This reveals that IFT also functions in maintaining the distribution of some flagellar proteins after construction of the organelle is completed.

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IFT27 Links the BBSome to IFT for Maintenance of the Ciliary Signaling Compartment

Cited by 239 publications

References 36 publications

Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Intraflagellar transport is required for the maintenance of the trypanosome flagellum composition but not its length

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