Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 24
Study of a molecular retrograde communication that involves SREBP-1 and SREBP-2 in
143 B cell responding to a lysosomal sucrose accumulation
Sophie Goblet1, Andrée Houbion2, Isabelle Hamer1, Laetitia Payen2, Marie-Jeanne
Vertez1, Michel Jadot1 and Thierry Arnould2
1. URPhyM : Unité de Recherche en Physiologie Moléculaire, Faculté de Médecine
(F.U.N.D.P.)
2. URBC : Unité de Recherche en Biologie Cellulaire, Faculté des Sciences (F.U.N.D.P)
61 rue de Bruxelles, 5000 Namur, Belgium. e-mail : thierry.arnould@fundp.ac.be
While numerous lysosomal diseases have been described to result from mutations in genes
encoding lysosomal hydrolases leading to lysosomal enzyme activity deficiency and/or
accumulation of non-hydrolysable substrates, cell signaling initiated by lysosomal storage
disorder is still poorly understood. We thus intended to identify new signaling pathway(s)
activated by a lysosomal storage of sucrose in human osteosarcoma cells (143B).
We found that these cells overexpress lysosomal markers in response to sucrose and we
characterized some aspects of the cell phenotype during sucrose accumulation. Among
several transcription factors studied, we next showed that members of SREBP (sterolresponsive
element binding protein) transcription factors are activated in response to a sucrose
lysosomal storage as luciferase reporter constructs driven by the FAS (fatty acid synthase),
HMG-CoA reductase, LDLR (low density lipoprotein receptor) promoters are found to be
activated in response to a sucrose incubation. We found that both SREBP-1 and SREBP-2
protein accumulate in the nucleus of the sucrose-treated cells. These data are supported by
findings showing that SREBP activation is correlated with a modification in cholesterol
distribution in the sucrose-treated cells as observed after a filipin staining. Furthermore, 25hydroxycholesterol
completely inhibits SREBP activation and dramatically reduces SREBP-2
abundance in the nucleus of sucrose-treated cells. We also investigated signaling pathways
that could lead to the activation or nuclear translocation of SREBP and found that SREBP
activation is sensitive to PI3-K and MEK1/2 inhibitors. Taken together, these data suggest
that lysosomal accumulation of a non-hydrolysable substrate such as sucrose, triggers the
activation of a cell signaling pathway leading to SREBP activation.
T. Arnould is a Research Associate of FNRS (Fonds National de la Recherche Scientifique,
Brussels, Belgium). S. Goblet is a recipient of a FRIA fellowship. We thank the governement
of the french-speaking community (Belgium) for financial support through an ARC
(Action de Recherche Concertée) programme.
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