Reconstitution reveals motor activation for intraflagellar transport

Mohamed, Mohamed A. A.; Stepp, Willi L.; Ökten, Zeynep

doi:10.1038/s41586-018-0105-3

Cited by 31 publications

(60 citation statements)

References 33 publications

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“…The proper assembly of the multi-component IFT complexes is required for IFT. Inhibiting the expression of IFT complex components is known to suppress IFT 10,19 . Therefore, to explore the mechanism underlying the decreasing IFT with ageing, we examined the expression of IFT components in WT worms at D1 and D10.…”

Section: Daf-19 Is Critical In the Ageing-induced Decline Of Ift And mentioning

confidence: 99%

The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing

Zhang

Dai

et al. 2020

Preprint

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Sensory perception and metabolic homeostasis deteriorate with ageing, impairing the health of aged animals. However, the mechanisms underlying their deterioration remain poorly understood. The potential interplay between the declining sensory perception and the impaired metabolism during ageing is also barely explored. Here, we report that the intraflagellar transport (IFT) in the cilia of sensory neurons is impaired in the aged nematode Caenorhabditis elegans due to a daf-19/RFX-modulated decrease of IFT components. The impaired IFT in sensory cilia in turn causes the deterioration of sensory perception with ageing. Moreover, whereas the IFT-dependent decrease of sensory perception in aged worms has a mild impact on the insulin/IGF-1 signalling, it remarkably suppresses AMP-activated protein kinase (AMPK) signalling across tissues. Upregulating daf-19/RFX effectively enhances IFT, sensory perception, AMPK activity and autophagy, promoting metabolic homeostasis and longevity. Our studies have uncovered an ageing pathway causing IFT decay and sensory perception deterioration, which in turn disrupts metabolism and healthy ageing.

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Section: Daf-19 Is Critical In the Ageing-induced Decline Of Ift And mentioning

confidence: 99%

The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing

Zhang

Dai

et al. 2020

Preprint

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“…The C. elegans kinesin-II and OSM-3-kinesin were expressed and purified as described previously (Brunnbauer et al, 2012;Mohamed et al, 2018). The setup of the optical tweezers was described (Brunnbauer et al, 2010;Gebhardt et al, 2010).…”

Section: Protein Preparation and Optical Tweezers Setupmentioning

confidence: 99%

Optimal sidestepping of intraflagellar transport kinesins regulates structure and function of sensory cilia

Xie

et al. 2020

The EMBO Journal

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Cytoskeletal‐based molecular motors produce force perpendicular to their direction of movement. However, it remains unknown whether and why motor proteins generate sidesteps movement along their filamentous tracks in vivo. Using Hessian structured illumination microscopy, we located green fluorescent protein (GFP)‐labeled intraflagellar transport (IFT) particles inside sensory cilia of live Caenorhabditis elegans with 3–6‐nanometer accuracy and 3.4‐ms resolution. We found that IFT particles took sidesteps along axoneme microtubules, demonstrating that IFT motors generate torque in a living animal. Kinesin‐II and OSM‐3‐kinesin collaboratively drive anterograde IFT. We showed that the deletion of kinesin‐II, a torque‐generating motor protein, reduced sidesteps, whereas the increase of neck flexibility of OSM‐3‐kinesin upregulated sidesteps. Either increase or decrease of sidesteps of IFT kinesins allowed ciliogenesis to the regular length, but changed IFT speeds, disrupted axonemal ninefold symmetry, and inhibited sensory cilia‐dependent animal behaviors. Thus, an optimum level of IFT kinesin sidestepping is associated with the structural and functional fidelity of cilia.

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“…These include, in addition to cell cycle 31 and cell division 19,20,32 , immune synapse polarization 17,18,33 , cell migration 34 and the regulation of cytoplasmic MT dynamics 16 or actin 35 . Future works will be required to address whether IFTs function in these non-ciliary roles only as cargo adaptors or also as motor regulators as shown for ciliary motors 15 .…”

Section: Discussionmentioning

confidence: 99%

IFT88 controls NuMA enrichment at k-fibers minus-ends to facilitate their reincorporation into mitotic spindles

Taulet

Douanier

Vitre

et al. 2019

Preprint

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To build and maintain mitotic spindle architecture, molecular motors exert spatially regulated forces on microtubules (MT) minus-ends. This spatial regulation is required to allow proper chromosomes alignment through the organization of kinetochore fibers (k-fibers). NuMA was recently shown to target dynactin to MT minus-ends and thus to spatially regulate dynein activity. However, given that k-fibers are embedded in the spindle, our understanding of the machinery involved in the targeting of proteins to their minus-ends remains limited. Intraflagellar transport (IFT) proteins were primarily studied for their ciliary roles but they also emerged as key regulators of cell division. Taking advantage of MT laser ablation, we show here that IFT88 concentrates at k-fibers minus-ends and is required for their re-anchoring into spindles by controlling NuMA accumulation. Indeed, IFT88 interacts with NuMA and is required for its enrichment at newly generated k-fibers minus-ends. Combining nocodazole washout experiments and IFT88 depletion, we further show that IFT88 is required for the reorganization of k-fibers into spindles and thus for efficient chromosomes alignment in mitosis. Overall, we propose that IFT88 could serve as a mitotic MT minus-end adaptor to concentrate NuMA at minus-ends thus facilitating kfibers incorporation into the main spindle.can be considered as a platform for such a regulation. Indeed, NuMA was recently shown to target dynactin to minus-ends and thus spatially regulate dynein activity 8,9 . If proteins recruitment at MT plus-end has been well-documented, the specific targeting of proteins to MTs and k-fiber minusends has yet to be fully understood 10 . Indeed, continuous reintegration of k-fibers happens inside an established spindle and is essential to preserve its integrity and to ensure proper chromosomes alignment 6-8 . However, given that k-fibers are embedded in the main spindle, our understanding of the machinery involved in the targeting of proteins to their minus-ends remains limited.The intraflagellar transport (IFT) machinery is a well conserved intra-cellular transport system that has been studied for a long time for its role in cilia formation and function in non-dividing cells 11 .During IFT-mediated transport, kinesin and dynein motors drive the bidirectional transport of IFT trains from the base to the tip of the cilium in an anterograde movement and from the tip to the base in a retrograde movement 12 . IFTs were therefore accepted to function as cargos, for example, of axoneme precursors such as tubulins as well as molecules of the signal transduction machinery inside the cilium 13,14 . More recently, IFTs were shown to contribute to ciliary motor activation 15 indicating that a lot remains to be done to fully understand the roles of this complex machinery. Interestingly, in addition to their ciliary roles, IFTs were also shown to function in interphase in the regulation of MT dynamics in the cytoplasm 16 . Moreover, they were shown to contribute to intracellular transport in n...

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Reconstitution reveals motor activation for intraflagellar transport

Cited by 31 publications

References 33 publications

The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing

The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing

Optimal sidestepping of intraflagellar transport kinesins regulates structure and function of sensory cilia

IFT88 controls NuMA enrichment at k-fibers minus-ends to facilitate their reincorporation into mitotic spindles

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