Article ; Online: Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways.
Proceedings of the National Academy of Sciences of the United States of America
2019 Volume 116, Issue 8, Page(s) 2977–2986
Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 ( ... ...
| Abstract | Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment. |
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| MeSH term(s) | Animals ; Autophagy/genetics ; Glycogen/biosynthesis ; Glycogen/genetics ; Glycogen Synthase Kinase 3 beta/genetics ; Humans ; Lysosomal-Associated Membrane Protein 1/genetics ; Lysosomal-Associated Membrane Protein 2/genetics ; Lysosomes/genetics ; Lysosomes/pathology ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mice ; Mutation ; Proteolysis ; Signal Transduction ; Tuberous Sclerosis/genetics ; Tuberous Sclerosis/pathology ; Tuberous Sclerosis Complex 2 Protein/genetics ; Ubiquitination/genetics |
| Chemical Substances | Lysosomal-Associated Membrane Protein 1 ; Lysosomal-Associated Membrane Protein 2 ; TSC2 protein, human ; Tuberous Sclerosis Complex 2 Protein ; Glycogen (9005-79-2) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2019-02-06 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 209104-5 |
| ISSN | 1091-6490 ; 0027-8424 |
| ISSN (online) | 1091-6490 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.1812943116 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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