O‐GlcNAcylation of FoxO1 in pancreatic β cells promotes Akt inhibition through an IGFBP1‐mediated autocrine mechanism. Issue 2 (30th October 2013)

• Record Type: Journal Article
• Authors: Fardini, Yann; Masson, Elodie; Boudah, Ouassila; Jouira, Rania Ben; Cosson, Camille; Pierre‐Eugene, Cécile; Kuo, Mei‐Shiue; Issad, Tarik
• Is Part Of: FASEB journal. Volume 28:Issue 2(2014)
• Page Start: 1010
• Page End: 1021
• Publication Date: 2013-10-30
• Subjects: insulin‐like growth factor‐binding protein 1 -- PI3K signaling -- glucotoxicity -- Forkhead transcription factor O1 -- apoptosis; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.13-238378
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : 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