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

Etienne Boulter (), Soline Estrach, Floriane S. Tissot, Marco L. Hennrich, Lionel Tosello, Laurence Cailleteau, Laura R. Ballina, Sabrina Pisano, Anne-Claude Gavin and Chloé C. Féral ()
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Etienne Boulter: Institute for Research on Cancer and Aging, Nice (IRCAN)
Soline Estrach: Institute for Research on Cancer and Aging, Nice (IRCAN)
Floriane S. Tissot: Institute for Research on Cancer and Aging, Nice (IRCAN)
Marco L. Hennrich: Structural and Computational Biology Unit
Lionel Tosello: Institute for Research on Cancer and Aging, Nice (IRCAN)
Laurence Cailleteau: Institute for Research on Cancer and Aging, Nice (IRCAN)
Laura R. Ballina: Institute for Research on Cancer and Aging, Nice (IRCAN)
Sabrina Pisano: Institute for Research on Cancer and Aging, Nice (IRCAN)
Anne-Claude Gavin: Structural and Computational Biology Unit
Chloé C. Féral: Institute for Research on Cancer and Aging, Nice (IRCAN)

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07268-w

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