Cofilin-Driven Nuclear Deformation Drives Dendritic Cell Migration through the Extracellular Matrix

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract To mount an adaptive immune response, dendritic cells must process antigens, migrate to lymph nodes and form synapses with T cells. Critical to 3D migration and mechano-sensing is the nucleus, which is the size-limiting barrier for navigation through gaps in the extracellular matrix. Here, we show that inflammatory activation of dendritic cells leads to the nucleus becoming spherically deformed, adopting a raison-like shape and enables dendritic cells to overcome the typical 2 – 3-micron pore limit for 3D-migration. We show that the nuclear shape-change is partially attained through reduced cell adhesion, whereas improved migration through extracellular matrix is achieved through reprogramming of the actin cytoskeleton. Specifically we show that cofilin-1 is phosphorylated at serine 41 drives the assembly of a Cofilin-ActoMyosin (CAM)-ring proximal to the nucleus and enhancing migration through 3D collagen gels. In summary, these data describe novel signaling events through which dendritic cells simultaneously deform their nucleus and enhance their migratory capacity; molecular events that may be re-capitulated in other contexts such as wound healing and cancer.

Authors 19

1. Harry M. Warner

   University of Groningen

   Affiliation as printed

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

2. Giulia Franciosa

   University of Copenhagen · Novo Nordisk Foundation

   Affiliation as printed

   Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University

   Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

3. Guus van der Borg

   University of Groningen · Zernike Institute for Advanced Materials

   Affiliation as printed

   Molecular Biophysics, Zernike Institute for Advanced Materials, University of Groningen

   Molecular Biophysics, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands

4. Felix Faas

   University of Groningen

   Affiliation as printed

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

5. Claire Koenig

   University of Copenhagen · Novo Nordisk Foundation

   Affiliation as printed

   Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University

   Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

6. Rinse de Boer

   University of Groningen

   Affiliation as printed

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

7. René Classens

   Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center

   Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, The Netherlands

8. Sjors Maassen

   University of Groningen

   Affiliation as printed

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

9. Maksim V. Baranov

   University of Groningen

   Affiliation as printed

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

   Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

10. Shweta Mahajan

    University of Groningen

    Affiliation as printed

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

11. Deepti Dabral

    University of Groningen

    Affiliation as printed

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

12. Britt A. Coenen

    University of Groningen

    Affiliation as printed

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

13. Frans Bianchi

    University of Groningen

    Affiliation as printed

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

14. Niek van Hilten Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University

    Leiden Institute of Chemistry, Leiden University, The Netherlands

15. Herre Jelger Risselada Aachen

    Leiden University · TU Dortmund University

    Affiliation as printed

    Department of Physics

    Leiden Institute of Chemistry, Leiden University

    Department of Physics, TU Dortmund, Dortmund, Germany

    Leiden Institute of Chemistry, Leiden University, The Netherlands

16. Wouter H. Roos

    University of Groningen · Zernike Institute for Advanced Materials

    Affiliation as printed

    Molecular Biophysics, Zernike Institute for Advanced Materials, University of Groningen

    Molecular Biophysics, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands

17. Jesper Velgaard Olsen

    University of Copenhagen · Novo Nordisk Foundation

    Affiliation as printed

    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University

    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

18. Laia Querol Cano

    Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

    Affiliation as printed

    Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center

    Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, The Netherlands

19. Geert van den Bogaart corresponding

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen

    Department of Pathology and Medical Biology, University Medical Center Groningen

    Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands

    Department of Pathology and Medical Biology, University Medical Center Groningen, the Netherlands