Résumé :
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In our laboratory, we have analyzed several mutations in the desmin gene found in patients suffering from desmin-related myopathies (DRM) (see related poster from Goudeau B et al.). Several of these mutations lead the formation of agregates of desmin after 72 hours of expression in cultured myoblasts, while it may take up to sixty years to manifest itself in the patient. To investigate how cells may protect themselves against the apparition of agregates, we undertook the study of the function of one small heat shock proteins (sHSPs), ?B-crystallin. In fact, sHSPs act as chaperone, but also in protecting the different cytoskeletal components like actin microfilaments or microtubules networks, and recent results suggest that ?B-crystallin also protects the integrity of intermediate filaments (IF) against extracellular stress (Djabali K. et al., J. Cell. Sci. 110 (1997) p2759 – 2769). We demonstrate that chronic perturbations of IF network by expressing mutated desmine molecules result in the activation of the p38/MAPKAP2 kinase pathway and lead to the specific ?B-crystallin phosphorylation at serine 59 (Launay N. et al., Exp. Cell Res. 312 (2006) p3570 – 3584). Upstream of p38, we found that RhoK, PKC and PKA are selectively involved in the activation of p38 and phosphorylation of ?B-crystallin upon desmin agregation. Finally, we also show that serine 59 phosphorylated ?B-crystallin colocalizes with cytoskeletal components, and displays a better protective function than the unphosphorylated ?B-crystallin. Thus, disturbance of cytoskeleton leads by converging signaling pathways to the phosphorylation of ?B-crystallin, which probably acts as a protective effector of the cytoskeleton.
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