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O ‐GlcNAcylation of FoxO1 in pancreatic β cells promotes Akt inhibition through an IGFBP1‐mediated autocrine mechanism
Author(s) -
Fardini Yann,
Masson Elodie,
Boudah Ouassila,
Jouira Rania Ben,
Cosson Camille,
PierreEugene Cécile,
Kuo MeiShiue,
Issad Tarik
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-238378
Subject(s) - foxo1 , protein kinase b , autocrine signalling , pi3k/akt/mtor pathway , chemistry , microbiology and biotechnology , signal transduction , biology , medicine , endocrinology , receptor , biochemistry
O ‐GlcNAcylation on serine/threonine is a post‐translational modification that controls the activity of nucleocytoplasmic proteins according to glucose availability. We previously showed that O ‐GlcNAcylation of FoxO1 in liver cells increases its transcriptional activity. In the present study, we evaluated the potential involvement of FoxO1 O ‐GlcNAcylation in the context of pancreatic β‐cell glucotoxicity. FoxO1 was O ‐GlcNAcylated in INS‐1 832/13 β cells and isolated rat pancreatic islets. O ‐GlcNAcylation of FoxO1 resulted in a 2‐fold increase in its transcriptional activity toward a FoxO1 reporter gene and a 3‐fold increase in the expression of the insulin‐like growth factor‐binding protein 1 (Igfbp1) gene at the mRNA level, resulting in IGFBP1 protein oversecretion by the cells. Of note, increased IGFBP1 in the culture medium inhibited the activity of the insulin‐like growth factor 1 receptor (IGF1R)/phosphatidyl inositol 3 kinase (PI3K)/Akt pathway. We reveal in this report a novel mechanism by which O ‐GlcNAcylation inhibits Akt activity through an autocrine mechanism. However, although inhibition of IGFBP1 expression using siRNA restored the PI3 kinase/Akt pathway, it did not rescue INS‐1 832/13 cells from high‐glucose‐ or O ‐glcNAcylation‐induced cell death. In contrast, FoxO1 down‐regulation by siRNA led to 30 to 60% protection of INS‐1 832/13 cells from death mediated by glucotoxic conditions. Therefore, whereas FoxO1 O ‐GlcNAcylation inhibits Akt through an IGFBP1‐mediated autocrine pathway, the deleterious effects of FoxO1 O ‐GlcNAcylation on cell survival appeared to be independent of this pathway.—Fardini, Y., Masson, E., Boudah, O., Ben Jouira, R., Cosson, C., Pierre‐Eugene, C., Kuo, M.‐S., Issad, T. O ‐GlcNAcylation of FoxO1 in pancreatic β cells promotes Akt inhibition through an IGFBP1‐mediated autocrine mechanism. FASEB J. 28, 1010–1021 (2014). www.fasebj.org