Regulation of Pgc1a expression by a Gsk3b-Tfeb signaling axis in skeletal muscle (WP4763)

Mus musculus

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In (skeletal) muscle cells, PGC-1 signaling controls mitochondrial biogenesis and oxidative substrate metabolism. PGC-1 signaling disturbance in skeletal muscle is linked to several chronic diseases. This pathway depicts the mechanism in which inhibition of GSK-3β increases Pgc-1α abundance, through dephosphorylation of Tfeb [https://doi.org/10.1016/j.bbamcr.2019.118610 Theeuwes et al, 2019]. This reaction allows Tfeb to translocate to the nucleus, where it stimulates the transcription of the PPARGC1A gene to the Pgc-1α protein. Phosphorylation of Tfeb leads to binding with members of the 14-3-3 protein family, which disables transport into the nucleus. If the dephosphorylation of Tfeb through Gsk-3β is a direct or indirect reaction is as of yet unknown.

Authors

Denise Slenter and Alex Pico

Activity

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Organisms

Mus musculus

Communities

Annotations

Pathway Ontology

peroxisome proliferator-activated receptor signaling pathway

Cell Type Ontology

skeletal muscle fiber

Participants

Label Type Compact URI Comment
CHIR99021 Metabolite pubchem.compound:9956119
PPARGC1A promotor GeneProduct ncbigene:19017 (Human Entrez Gene: 10891)
14-3-3 protein family Protein interpro:IPR000308
Gsk-3β Protein uniprot:Q9WV60 AKA glycogen synthase kinase (GSK)-3β (Human Uniprot: P49841)
Tfeb Protein uniprot:Q9R210 transcription factor EB (TFEB)
Pgc-1α Protein uniprot:O70343 (Human Uniprot: Q9UBK2)
Tfeb Protein uniprot:Q9R210 transcription factor EB (TFEB) (Human Uniprot: P19484)

References

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  4. YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization. Xu Y, Ren J, He X, Chen H, Wei T, Feng W. Autophagy. 2019 Jun;15(6):1017–30. PubMed Europe PMC Scholia
  5. Regulation of PGC-1α expression by a GSK-3β-TFEB signaling axis in skeletal muscle. Theeuwes WF, Gosker HR, Schols AMWJ, Langen RCJ, Remels AHV. Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118610. PubMed Europe PMC Scholia