Hemidesmosomes modulate force generation via focal adhesions

The Journal of Cell Biology, vol. 219

Abstract

Hemidesmosomes are specialized cell-matrix adhesion structures that are associated with the keratin cytoskeleton. Although the adhesion function of hemidesmosomes has been extensively studied, their role in mechanosignaling and transduction remains largely unexplored. Here, we show that keratinocytes lacking hemidesmosomal integrin α6β4 exhibit increased focal adhesion formation, cell spreading, and traction-force generation. Moreover, disruption of the interaction between α6β4 and intermediate filaments or laminin-332 results in similar phenotypical changes. We further demonstrate that integrin α6β4 regulates the activity of the mechanosensitive transcriptional regulator YAP through inhibition of Rho-ROCK-MLC- and FAK-PI3K-dependent signaling pathways. Additionally, increased tension caused by impaired hemidesmosome assembly leads to a redistribution of integrin αVβ5 from clathrin lattices to focal adhesions. Our results reveal a novel role for hemidesmosomes as regulators of cellular mechanical forces and establish the existence of a mechanical coupling between adhesion complexes.

Authors 8

1. Wei Wang

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands 1

2. Alba Zuidema

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands 1

3. Lisa te Molder

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands 1

4. Leila Nahidiazar

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands 1

5. Liesbeth Hoekman

   The Netherlands Cancer Institute

   Affiliation as printed

   Mass Spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, Netherlands 2

6. Thomas Schmidt Aachen Physics of Life Processes Huygens-Kamerlingh Onnes Laboratory

   Leiden University

   Affiliation as printed

   Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Leiden, Netherlands 3

7. Stefano Coppola Aachen Physics of Life Processes Huygens-Kamerlingh Onnes Laboratory

   Leiden University

   Affiliation as printed

   Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Leiden, Netherlands 3

8. Arnoud Sonnenberg corresponding

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands 1