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Accueil du site > Equipes de recherche > Signalisation calcique > Thèmes de recherche > Sphingolipids signalling and cell death : regulation by calcium

Sphingolipids signalling and cell death : regulation by calcium

Contacts : mail to Valérie COTELLE, mail to Christian MAZARS, mail to Patrice THULEAU

Our previous nuclear calcium signaling studies led us to consider the sphingolipids as potential activators of nuclear calcium channels because these molecules were shown to be agonists of TRPM-type calcium channels in animals (Grimm et al., 2005). The specific class of sphingolipids called Long Chain Bases (LCBs) which are precursors of ceramides and more complex sphingolipids, are now accepted as signaling molecules controlling the cell fate in eukaryotes. Indeed, they have been shown by us and others to be able to induce cell death and/or hypersensitive response (HR)-like symptoms when applied to plants or cell cultures. In this context , LCBs have been proposed to be involved in plant immunity (Peer et al. 2010). On this basis, our group demonstrated that the two most abundant LCBs in plants, phytosphingosine and dihydrosphingosine, are equally active in inducing programmed cell death (PCD) either in tobacco or Arabidopsis cells. Similarly, natural sphingolipid derivatives, such as the mycotoxin fumonisin B1 (FB1), also induce PCD in infiltrated leaves of the wild type A. thaliana Col0 accession. Our group has contributed to describe the earliest signaling events associated to LCB or FB1 perception. Thus, following LCB or FB1 application, an immediate rise in calcium occurs in the cytosol concomitantly with an increase in the endogenous content of LCBs followed by a delayed increase in calcium concentration in the nucleus. Simultaneously, reactive oxygen species (ROS) and nitric oxide (NO) burst are also produced. A pharmacological approach led us to demonstrate that nuclear calcium increases are required for the full development of PCD symptoms (Lachaud et al. 2010) whereas ROS and NO are not required (Lachaud et al. 2011, Da Silva et al. 2011). Increase in cell calcium concentration activates a specific calcium-dependent protein kinase (CPK3) which in turn phosphorylates a specific serine residue located at the dimerization site of a 14-3-3 dimer itself sequestering CPK3. Upon phosphorylation, the 14-3-3 dimer dissociates allowing the release of CPK3 and its subsequent proteolysis. By a reverse genetic approach using cpk3 knock-out mutants, we demonstrated the physiological relevance of this CPK as a positive regulator of mycotoxin-induced PCD (Lachaud et al. 2013).

Concomitantly to the NO increase observed in response to LCB treatment of tobacco cells, we observed an accumulation of glyceraldehyde-3-phosphate deshydrogenases (GAPDH) in the nucleus where it is found to be S-nitrosylated.

Altogether, our results led us to propose the current model :

Focusing on the plant model Arabidopsis, our current and future objectives are

  1. To understand how calcium and its compartmentalization may control, via protein-protein interactions (14-3-3s –CPK3) and phosphorylation events, the sphingolipid pathway leading to cell death
  2. To characterize the regulatory processes and the role of 14-3-3 proteins and their targets in the LCB-induced PCD.
  3. To unravel the role of GAPDH in this process and how its role is achieved.


Le Ru A. :

Xiong T.C. :

Boudsocq M. :

Van der Hoorn R. :

Related references (external)

Grimm C, Kraft R, Schultz G, Harteneck C. (2005). Activation of the melastatin-related cation channel TRPM3 by D-erythro-sphingosine [corrected]. Mol Pharmacol. 67(3):798-805

Related references (group)

Ranty B, Aldon D, Cotelle V, Galaud JP, Thuleau P, Mazars C. (2016) Calcium sensors as key hubs in plant responses to biotic and abiotic stresses. Front. Plant Sci 7 : 327

Cotelle V, Leonhardt N. (2016). 14-3-3 proteins in guard cell signaling. Front. Plant Sci. 6:12

Lachaud C, Prigent E, Thuleau P, Grat S, Da Silva D, Brière C, Mazars C, Cotelle V. (2013). 14-3-3-regulated Ca(2+)-dependent protein kinase CPK3 is required for sphingolipid-induced cell death in Arabidopsis. Cell Death Differ. 20(2):209-17

Thuleau P, Aldon D, Cotelle V, Brière C, Ranty B, Galaud JP, Mazars C. (2013) Relationships between calcium and sphingolipid-dependent signalling pathways during the early steps of plant-pathogen interactions. Biochim Biophys Acta. 7:1590-4.

Da Silva D, Lachaud C, Cotelle V, Brière C, Grat S, Mazars C, Thuleau P. (2011) Nitric oxide production is not required for dihydrosphingosine-induced cell death in tobacco BY-2 cells. Plant Signal Behav. 6(5):736-9.

Lachaud C, Da Silva D, Cotelle V, Thuleau P, Xiong TC, Jauneau A, Brière C, Graziana A, Bellec Y, Faure JD, Ranjeva R, Mazars C. (2011). Nuclear calcium controls the apoptotic-like cell death induced by d-erythro-sphinganine in tobacco cells. Cell Calcium. 47(1):92-100.

Lachaud C, Da Silva D, Amelot N, Béziat C, Brière C, Cotelle V, Graziana A, Grat S, Mazars C, Thuleau P. (2011). Dihydrosphingosine-induced programmed cell death in tobacco BY-2 cells is independent of H₂O₂ production .Mol Plant. 4(2):310-8.

Xiong TC, Coursol S, Grat S, Ranjeva R, Mazars C.(2008) Sphingolipid metabolites selectively elicit increases in nuclear calcium concentration in cell suspension cultures and in isolated nuclei of tobacco. Cell Calcium. (1):29-37.