TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy
| Autor: | Xiaolei Xu, Linghui Lu, Alexey V. Dvornikov, Xueying Lin, Xiao Ma, Maengjo Kim, Timothy M. Olson, Yonghe Ding, Ping Zhu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiomyopathy mTORC1 030204 cardiovascular system & hematology medicine.disease_cause Gene Knockout Techniques Mice 0302 clinical medicine Myocytes Cardiac Gene Knock-In Techniques Biology (General) Zebrafish Cells Cultured Spectroscopy Mutation biology Basic Helix-Loop-Helix Leucine Zipper Transcription Factors TOR Serine-Threonine Kinases RagCS75Y General Medicine Phenotype Recombinant Proteins Computer Science Applications Chemistry Gain of Function Mutation mTOR Signal Transduction Cardiomyopathy Dilated QH301-705.5 Heart Ventricles Active Transport Cell Nucleus Mutation Missense Article Catalysis Inorganic Chemistry 03 medical and health sciences Transcription Activator-Like Effector Nucleases Autophagy medicine Animals Humans Point Mutation Rats Wistar Physical and Theoretical Chemistry Molecular Biology QD1-999 PI3K/AKT/mTOR pathway Monomeric GTP-Binding Proteins TFEB Base Sequence Organic Chemistry Zebrafish Proteins biology.organism_classification medicine.disease 030104 developmental biology Amino Acid Substitution Cancer research Rags cardiomyopathy |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 5494, p 5494 (2021) International Journal of Molecular Sciences Volume 22 Issue 11 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagCS75Y) knock-in (KI) line via TALEN technology. The KI fish manifested cardiomyopathy-like phenotypes and poor survival. Overexpression of RagCS75Y via adenovirus infection also led to increased cell size and fetal gene reprogramming in neonatal rat ventricle cardiomyocytes (NRVCMs), indicating a conserved mechanism. Further characterization identified aberrant mammalian target of rapamycin complex 1 (mTORC1) and transcription factor EB (TFEB) signaling, as well as metabolic abnormalities including dysregulated autophagy. However, mTOR inhibition failed to ameliorate cardiac phenotypes in the RagCS75Y cardiomyopathy models, concomitant with a failure to promote TFEB nuclear translocation. This observation was at least partially explained by increased and mTOR-independent physical interaction between RagCS75Y and TFEB in the cytosol. Importantly, TFEB overexpression resulted in more nuclear TFEB and rescued cardiomyopathy phenotypes. These findings suggest that S75Y is a pathogenic gain-of-function mutation in RagC that leads to cardiomyopathy. A primary pathological step of RagCS75Y cardiomyopathy is defective mTOR–TFEB signaling, which can be corrected by TFEB overexpression, but not mTOR inhibition. |
| Databáze: | OpenAIRE |
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