ABSTRACT
Cell migration is central to evoking a potent immune response. Dendritic cell (DC) migration to lymph nodes is dependent on the interaction of C-type lectin-like receptor 2 (CLEC-2; encoded by the gene Clec1b), expressed by DCs, with podoplanin, expressed by lymph node stromal cells, although the underlying molecular mechanisms remain elusive. Here, we show that CLEC-2-dependent DC migration is controlled by tetraspanin CD37, a membrane-organizing protein. We identified a specific interaction between CLEC-2 and CD37, and myeloid cells lacking CD37 (Cd37−/−) expressed reduced surface CLEC-2. CLEC-2-expressing Cd37−/− DCs showed impaired adhesion, migration velocity and displacement on lymph node stromal cells. Moreover, Cd37−/− DCs failed to form actin protrusions in a 3D collagen matrix upon podoplanin-induced CLEC-2 stimulation, phenocopying CLEC-2-deficient DCs. Microcontact printing experiments revealed that CD37 is required for CLEC-2 recruitment in the membrane to its ligand podoplanin. Finally, Cd37−/− DCs failed to inhibit actomyosin contractility in lymph node stromal cells, thus phenocopying CLEC-2-deficient DCs. This study demonstrates that tetraspanin CD37 controls CLEC-2 membrane organization and provides new molecular insights into the mechanisms underlying CLEC-2-dependent DC migration.
This article has an associated First Person interview with the first author of the paper.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: C.M.d.W., S.v.D., M.G.T., S.E.A., A.B.v.S.; Methodology: C.M.d.W., M.G.T., S.E.A., A.B.v.S.; Validation: C.M.d.W., A.L.M.; Formal analysis: C.M.d.W., A.L.M.; Investigation: C.M.d.W., A.L.M., A.v.d.S., N.D.T., E.J., H.M.M., S.E.A.; Resources: J.A.E., B.N., H.M.M., S.E.A.; Writing - original draft: C.M.d.W.; Writing - review & editing: A.L.M., S.v.D., H.M.M., M.G.T., S.E.A., A.B.v.S.; Visualization: C.M.d.W., A.L.M.; Supervision: C.G.F., M.G.T., S.E.A., A.B.v.S.; Funding acquisition: C.M.d.W., A.L.M., H.M.M., C.G.F., M.G.T., S.E.A., A.B.v.S.
Funding
This work was supported by Erasmus+ [Staff Mobility Grant to C.M.d.W.], Nederlandse Organisatie voor Wetenschappelijk Onderzoek [019.162LW.004 to C.M.d.W.; Scientific Research Spinoza Award to C.G.F.; 864.11.006 and ICI-024.002.009 to A.B.v.S.], the Biotechnology and Biological Sciences Research Council [PhD Studentship to A.L.M.], the Medical Research Council [PhD Studentship to N.D.T.; G0400247 to M.G.T.; MC_U12266B to S.E.A.], Deutsche Forschungsgemeinschaft [SFB1009 A09 to J.A.E.; SFB/TR 240 to B.N.], Arthritis Research UK [19899 to H.M.M.], the European Research Council [269019 to C.G.F.; 724281 to A.B.v.S.], KWF Kankerbestrijding [KUN2009-4402 to C.G.F.; KUN2014-6845 to A.B.v.S.], the British Heart Foundation [FS/08/062/25797 to M.G.T.] and Cancer Research UK [CRUK-A19763 to S.E.A.].
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.214551.supplemental
- Received January 2, 2018.
- Accepted August 23, 2018.
- © 2018. Published by The Company of Biologists Ltd
Log in using your username and password
Log in through your institution
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$30.00 .
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
Article navigation
Related articles
Cited by...
More in this TOC section
Similar articles
Other journals from The Company of Biologists
In memoriam – Ian Moore
It is with great sadness that Chris Hawes writes the obituary of Ian Moore, Associate Professor in Plant Sciences and Fellow of Wadham College, University of Oxford. Ian succumbed to cancer in August. He made major contributions to plant molecular biology, gene expression systems, the secretory pathway and plant development.
Featured article - Identification and characterization of genes encoding the nuclear envelope LINC complex in the monocot species Zea mays
This Accepted Manuscript is about the plant nuclear envelope in a model grass species. Hank Bass talks about the working model his team propose for the entire maize LINC (Linker of Nucleoskeleton to Cytoskeleton) complex.
Condensins and cohesins generate intramolecular DNA loops. Robert Skibbens explains how condensin rods extrude DNA to compact chromatin during mitosis, whereas structurally adaptive cohesin rings organize the genome during interphase to regulate gene transcription.
Franziska Lautenschläger - credit to Iris Maurer
“Having children forces you to make a clean cut between work and home, and I feel this can be very beneficial because you are forced to think about something else.”
Franziska Lautenschläger’s research focuses on cell migration and polarity, and the links to cell mechanics and the different cytoskeletal networks in cells. Franziska holds a junior professorship in biophysics and is a group leader at both Saarland University and the Leibniz Institute for New Materials in Saarbrücken, Germany.
Want to put organising a Workshop on your CV? We are currently seeking proposals for Workshops to be held during 2021. You can watch this video to hear from some of our previous organisers. Next deadline for applications: 31 May 2019.
Journal of Cell Science is pleased to welcome submissions for an upcoming special issue on 'Cell Biology of the Immune System' edited by Ana-Maria Lennon-Duménil. We invite you to showcase your breakthrough research on all aspects of cell biology as it relates to the immune system. The articles within this issue will receive extensive exposure to a broad audience of cell biologists and immunologists. Submission deadline: 30 June 2019.
First Person interviews
Have you seen our First Person interviews with the early-career first authors of our papers? The authors talk about their work in and out of the lab, the journeys that led them to where they are now and the scientists who inspired them along the way. Recently, we caught up with first authors Yang Li and Chelsea Merkel, Tyler Picariello and Hardeep Gumber.
preLights – A complex containing lysine-acetylated actin inhibits the formin INF2
Laura McCormick highlights a recent preprint from Henry Higgs and team which uses some old-school biochemistry techniques to identify a cellular factor that facilitates INF2 auto-inhibition.
Catch up with recent preLights selected for the cell science community in our latest Table of Contents.
Articles of interest in our sister journals
A crucial role for Arf6 in the response of commissural axons to Slit
Mariko Kinoshita-Kawada, Hiroshi Hasegawa, Tsunaki Hongu, Shigeru Yanagi, Yasunori Kanaho, Ichiro Masai, Takayasu Mishima, Xiaoping Chen, Yoshio Tsuboi, Yi Rao, Junichi Yuasa-Kawada, Jane Y. Wu
Development 2019 146: dev172106
Rab23/Kif17 regulate meiotic progression in oocytes by modulating tubulin acetylation and actin dynamics
Hong-Hui Wang, Yu Zhang, Feng Tang, Meng-Hao Pan, Xiang Wan, Xiao-Han Li, Shao-Chen Sun
Development 2019 146: dev171280