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Hot-wiring dynein-2 uncovers roles for IFT-A in retrograde train assembly and motility

Francisco Gonçalves-Santos, Ana R. G. De-Castro, Diogo R. M. Rodrigues, Maria J. G. De-Castro, Reto Gassmann, View ORCID ProfileCarla M. C. Abreu, View ORCID ProfileTiago J. Dantas
doi: https://doi.org/10.1101/2023.05.10.539247
Francisco Gonçalves-Santos
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
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Ana R. G. De-Castro
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
3ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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Diogo R. M. Rodrigues
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
3ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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Maria J. G. De-Castro
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
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Reto Gassmann
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
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Carla M. C. Abreu
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
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  • For correspondence: carla.abreu@i3s.up.pt tiago.dantas@i3s.up.pt
Tiago J. Dantas
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
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  • ORCID record for Tiago J. Dantas
  • For correspondence: carla.abreu@i3s.up.pt tiago.dantas@i3s.up.pt
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SUMMARY

Intraflagellar transport (IFT) trains, built around IFT-A and IFT-B complexes, are carried by opposing motors to import and export ciliary cargo. While transported by kinesin-2 on anterograde IFT trains, the dynein-2 motor adopts an autoinhibitory conformation until it needs to be activated at the ciliary tip to power retrograde IFT. Growing evidence has linked the IFT-A complex to retrograde IFT; however, its roles in this process remain unknown.

Here, we used CRISPR/Cas9-mediated editing to disable the dynein-2 autoinhibition mechanism in Caenorhabditis elegans, and assessed its impact on IFT with high-resolution live imaging and photobleaching analyses. Remarkably, this dynein-2 “hot-wiring” approach reignites retrograde motility inside IFT-A-deficient cilia, without triggering tug-of-war events. In addition to providing functional evidence that multiple mechanisms maintain dynein-2 inhibited during anterograde IFT, our data uncover key roles for IFT-A in: mediating motor-train coupling during IFT turnaround; promoting retrograde IFT initiation; and modulating dynein-2 retrograde motility.

Highlights

  • - Hot-wiring mutations enable dynein-2 to undergo retrograde movement in IFT-A-deficient cilia

  • - Disabling dynein-2 autoinhibition reveals that multiple mechanisms restrain dynein-2 activity during anterograde IFT

  • - IFT-A promotes retrograde IFT initiation and efficient dynein-2 motility

  • - IFT-A mediates dynein-2 coupling to retrograde IFT trains

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵4 Lead contact: Tiago J. Dantas

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 10, 2023.
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Hot-wiring dynein-2 uncovers roles for IFT-A in retrograde train assembly and motility
Francisco Gonçalves-Santos, Ana R. G. De-Castro, Diogo R. M. Rodrigues, Maria J. G. De-Castro, Reto Gassmann, Carla M. C. Abreu, Tiago J. Dantas
bioRxiv 2023.05.10.539247; doi: https://doi.org/10.1101/2023.05.10.539247
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Hot-wiring dynein-2 uncovers roles for IFT-A in retrograde train assembly and motility
Francisco Gonçalves-Santos, Ana R. G. De-Castro, Diogo R. M. Rodrigues, Maria J. G. De-Castro, Reto Gassmann, Carla M. C. Abreu, Tiago J. Dantas
bioRxiv 2023.05.10.539247; doi: https://doi.org/10.1101/2023.05.10.539247

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