PUBLICATION
TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy
- Authors
- Kim, M., Lu, L., Dvornikov, A.V., Ma, X., Ding, Y., Zhu, P., Olson, T.M., Lin, X., Xu, X.
- ID
- ZDB-PUB-210603-33
- Date
- 2021
- Source
- International Journal of Molecular Sciences 22(11): (Journal)
- Registered Authors
- Ding, Yonghe, Lin, Xueying, Xu, Xiaolei, Zhu, Ping
- Keywords
- RagCS75Y, Rags, TFEB, cardiomyopathy, mTOR
- MeSH Terms
-
- TOR Serine-Threonine Kinases/antagonists & inhibitors*
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/physiology*
- Zebrafish
- Mutation, Missense*
- Active Transport, Cell Nucleus
- Myocytes, Cardiac/metabolism
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology
- Base Sequence
- Cells, Cultured
- Cardiomyopathy, Dilated/genetics*
- Cardiomyopathy, Dilated/therapy
- Humans
- Rats, Wistar
- Point Mutation*
- Transcription Activator-Like Effector Nucleases
- Phenotype
- Recombinant Proteins/metabolism
- Monomeric GTP-Binding Proteins/genetics*
- Monomeric GTP-Binding Proteins/physiology
- Signal Transduction
- Amino Acid Substitution
- Heart Ventricles/cytology
- Mice
- Animals
- Autophagy
- Gene Knockout Techniques
- Gain of Function Mutation*
- Gene Knock-In Techniques
- PubMed
- 34071043 Full text @ Int. J. Mol. Sci.
Citation
Kim, M., Lu, L., Dvornikov, A.V., Ma, X., Ding, Y., Zhu, P., Olson, T.M., Lin, X., Xu, X. (2021) TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy. International Journal of Molecular Sciences. 22(11):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping