Msc Gradutae seminar-Sewar Zbidat
10/02/2021 13:00

Insulinreceptor turnover in fasting is dependent on b-dystroglycan deglycosylation

Fasting exertsvarious physiological effects, most notably, reduced signaling through theinsulin receptor. Insulin receptor activity requires association withDystrophin Glycoprotein Complex (DGC), and fasting induces autophagic clearanceof this co-assembly. We showed that insulin receptor turnover during fastingrequires deglycosylation of b-dystroglycan.Removal of N-linked glycans on b-dystroglycanis catalyzed by the lysosomal enzymes HexA and Man2b1 because theirdownregulation in atrophying muscles prevented b-dystroglycandeglycosylation and insulin receptor-DGC loss. Surprisingly, the lysosomalenzyme NAGLU, which cannot process N-linked glycosylation, also facilitated b-dystroglycan deglycosylation and insulinreceptor loss. Furthermore, Man2b1 andHexA were induced in fasting by the transcriptional complex PPAR-g/RXR-a, but not whenNAGLU or RXR-a were downregulated.By promoting PPAR-g O-GlcNAcylation,NAGLU facilitates PPAR-g/RXR-a-mediated Man2b1 and HexA induction and b-dystroglycandeglycosylation. Accordingly, downregulation of NAGLU or RXR-a during fasting blocked b-dystroglycan deglycosylation, and consequentlyinsulin receptor-DGC co-assemblies accumulated on the muscle membrane. Thus,NAGLU mediates physiological adaptation to fasting by promoting b-dystroglycan deglycosylation.

The seminarwill be given in English

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