Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway

Etienne Boulter,Anne-Claude Gavin,Soline Estrach,Floriane S Tissot,Sabrina Pisano,Marco L Hennrich,Chloé C Féral,Lionel Tosello,Laurence Cailleteau,Laura R De La Ballina

doi:10.1038/s41467-018-07268-w

Abstract

Mechanical and metabolic cues independently contribute to the regulation of cell and tissue homeostasis. However, how they cross-regulate each other during this process remains largely unknown. Here, we show that cellular metabolism can regulate integrin rigidity-sensing via the sphingolipid metabolic pathway controlled by the amino acid transporter and integrin coreceptor CD98hc (SLC3A2). Genetic invalidation of CD98hc in dermal cells and tissue impairs rigidity sensing and mechanical signaling downstream of integrins, including RhoA activation, resulting in aberrant tissue mechanical homeostasis. Unexpectedly, we found that this regulation does not occur directly through regulation of integrins by CD98hc but indirectly, via the regulation of sphingolipid synthesis and the delta-4-desaturase DES2. Loss of CD98hc decreases sphingolipid availability preventing proper membrane recruitment, shuttling and activation of upstream regulators of RhoA including Src kinases and GEF-H1. Altogether, our results unravel a novel cross-talk regulation between integrin mechanosensing and cellular metabolism which may constitute an important new regulatory framework contributing to mechanical homeostasis.

Highlights

Mechanical and metabolic cues independently contribute to the regulation of cell and tissue homeostasis
In order to assess whether CD98hc regulates integrin mechanosensing, we monitored cell stiffening using fibronectin (FN)-coated paramagnetic beads coupled to magnetic tweezers to sequentially apply forces on cells and assess their stiffening by tracking bead movement[19]
In the present study, we characterize a novel function for CD98hc as a regulator of integrin mechanosensing but foremost, we uncover an unanticipated cross-regulatory mechanism between cell metabolism and integrin mechanosensing regulated by the integrin coreceptor and amino acid transporter CD98hc (SLC3A2)

Summary

Introduction

Mechanical and metabolic cues independently contribute to the regulation of cell and tissue homeostasis. We show that depletion of CD98hc in cells impairs rigidity sensing and mechanical signaling downstream of integrins, including RhoA activation. Force application triggered RhoA activation as early as 1min whereas it barely stimulated RhoA in CD98hc-null cells (Fig. 1c and Supplementary Fig. 1j).

Results

Conclusion