Cargando…

Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease

Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD—laforin phosphatase and malin ubiquitin ligase—are believed to be inv...

Descripción completa

Detalles Bibliográficos
Autores principales: Singh, Pankaj Kumar, Singh, Sweta, Ganesh, Subramaniam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861076/
https://www.ncbi.nlm.nih.gov/pubmed/24131995
http://dx.doi.org/10.1091/mbc.E13-05-0261
_version_ 1782295591912472576
author Singh, Pankaj Kumar
Singh, Sweta
Ganesh, Subramaniam
author_facet Singh, Pankaj Kumar
Singh, Sweta
Ganesh, Subramaniam
author_sort Singh, Pankaj Kumar
collection PubMed
description Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD—laforin phosphatase and malin ubiquitin ligase—are believed to be involved in glycogen metabolism. We earlier demonstrated that laforin and malin negatively regulate cellular glucose uptake by preventing plasma membrane targeting of glucose transporters. We show here that loss of laforin results in activation of serum/glucocorticoid-induced kinase 1 (SGK1) in cellular and animals models and that inhibition of SGK1 in laforin-deficient cells reduces the level of plasma membrane-bound glucose transporter, glucose uptake, and the consequent glycogen accumulation. We also provide evidence to suggest that mammalian target of rapamycin (mTOR) activates SGK1 kinase in laforin-deficient cells. The mTOR activation appears to be a glucose-dependent event, and overexpression of dominant-negative SGK1 suppresses mTOR activation, suggesting the existence of a feedforward loop between SGK1 and mTOR. Our findings indicate that inhibition of SGK1 activity could be an effective therapeutic approach to suppress glycogen accumulation, inhibit mTOR activity, and rescue autophagy defects in LD.
format Online
Article
Text
id pubmed-3861076
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-38610762014-03-02 Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease Singh, Pankaj Kumar Singh, Sweta Ganesh, Subramaniam Mol Biol Cell Articles Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD—laforin phosphatase and malin ubiquitin ligase—are believed to be involved in glycogen metabolism. We earlier demonstrated that laforin and malin negatively regulate cellular glucose uptake by preventing plasma membrane targeting of glucose transporters. We show here that loss of laforin results in activation of serum/glucocorticoid-induced kinase 1 (SGK1) in cellular and animals models and that inhibition of SGK1 in laforin-deficient cells reduces the level of plasma membrane-bound glucose transporter, glucose uptake, and the consequent glycogen accumulation. We also provide evidence to suggest that mammalian target of rapamycin (mTOR) activates SGK1 kinase in laforin-deficient cells. The mTOR activation appears to be a glucose-dependent event, and overexpression of dominant-negative SGK1 suppresses mTOR activation, suggesting the existence of a feedforward loop between SGK1 and mTOR. Our findings indicate that inhibition of SGK1 activity could be an effective therapeutic approach to suppress glycogen accumulation, inhibit mTOR activity, and rescue autophagy defects in LD. The American Society for Cell Biology 2013-12-15 /pmc/articles/PMC3861076/ /pubmed/24131995 http://dx.doi.org/10.1091/mbc.E13-05-0261 Text en © 2013 Singh et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Singh, Pankaj Kumar
Singh, Sweta
Ganesh, Subramaniam
Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
title Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
title_full Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
title_fullStr Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
title_full_unstemmed Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
title_short Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
title_sort activation of serum/glucocorticoid-induced kinase 1 (sgk1) underlies increased glycogen levels, mtor activation, and autophagy defects in lafora disease
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861076/
https://www.ncbi.nlm.nih.gov/pubmed/24131995
http://dx.doi.org/10.1091/mbc.E13-05-0261
work_keys_str_mv AT singhpankajkumar activationofserumglucocorticoidinducedkinase1sgk1underliesincreasedglycogenlevelsmtoractivationandautophagydefectsinlaforadisease
AT singhsweta activationofserumglucocorticoidinducedkinase1sgk1underliesincreasedglycogenlevelsmtoractivationandautophagydefectsinlaforadisease
AT ganeshsubramaniam activationofserumglucocorticoidinducedkinase1sgk1underliesincreasedglycogenlevelsmtoractivationandautophagydefectsinlaforadisease