C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases

Ji, Yon Ju; Ugolino, Janet; Zhang, Tao; Lu, Jun; Kim, Dohoon; Wang, Jiou

doi:10.1371/journal.pgen.1008738

Cited by 18 publications

(22 citation statements)

References 64 publications

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“…Helix-Loop-Helix-30 (HLH-30), the TFEB ortholog as transcriptional switches, couple autophagy and lysosomal lipolysis to nutritional changes through mediating the efficient lipid clearance in Caenorhabditis Elegans, resulting in additive effects with controlling fat storage ( O’Rourke and Ruvkun, 2013 ; Franco-Juárez et al, 2018 ). In agreement with this, a similar conserved pathway is replicable in human cells ( Ji et al, 2020 ) and murine models ( Visvikis et al, 2014 ; Nakamura and Yoshimori, 2018 ), underscoring that HLH-30 or TFEB is conservative in linking autophagy to lipid homeostasis and lifespan. There are also reports for regulation by TFEB of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) ( Finck and Kelly, 2006 ) and peroxisome proliferator-activated receptor α (PPARα) ( Tan H. W. S. et al, 2019 ), the main regulatory factors of lipid metabolism.…”

Section: The Function and Molecular Mechanism Of Tfeb Regulating Lipisupporting

confidence: 64%

TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis

Wang

et al. 2021

Front. Physiol.

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Atherosclerosis, predominantly characterized by the disturbance of lipid homeostasis, has become the main causation of various cardiovascular diseases. Therefore, there is an urgent requirement to explore efficacious targets that act as lipid modulators for atherosclerosis. Transcription factor EB (TFEB), whose activity depends on post-translational modifications, such as phosphorylation, acetylation, SUMOylation, ubiquitination, etc., is significant for normal cell physiology. Recently, increasing evidence implicates a role of TFEB in lipid homeostasis, via its functionality of promoting lipid degradation and efflux through mediating lipophagy, lipolysis, and lipid metabolism-related genes. Furthermore, a regulatory effect on lipid transporters and lipid mediators by TFEB is emerging. Notably, TFEB makes a possible therapeutic target of atherosclerosis by regulating lipid metabolism. This review recapitulates the update and current advances on TFEB mediating lipid metabolism to focus on two intracellular activities: a) how cells perceive external stimuli and initiate transcription programs to modulate TFEB function, and b) how TFEB restores lipid homeostasis in the atherosclerotic process. In-depth research is warranted to develop potent agents against TFEB to alleviate or reverse the progression of atherosclerosis.

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Section: The Function and Molecular Mechanism Of Tfeb Regulating Lipisupporting

confidence: 64%

TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis

Wang

et al. 2021

Front. Physiol.

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“…Non-neuronally, these worms have an endocytosis defect that can be partially rescued by introducing wild-type human C9orf72 ( Corrionero and Horvitz, 2018 ). C. elegans alfa-1 has also been reported to be involved in nutrient sensing and metabolic control ( Ji et al, 2020 ).…”

Section: Genetic Models Of Neurodegenerationmentioning

confidence: 99%

Modeling neurodegeneration in Caenorhabditis elegans

Caldwell

Willicott

2020

Disease Models &Amp; Mechanisms

107

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The global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The nematode Caenorhabditis elegans has served as the experimental subject for multiple transformative discoveries that have redefined our understanding of biology for ∼60 years. More recently, the considerable attributes of C. elegans have been applied to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. Transgenic nematodes with genes encoding normal and disease variants of proteins at the single- or multi-copy level under neuronal-specific promoters limits expression to select neuronal subtypes. The anatomical transparency of C. elegans affords the use of co-expressed fluorescent proteins to follow the progression of neurodegeneration as the animals age. Significantly, a completely defined connectome facilitates detailed understanding of the impact of neurodegeneration on organismal health and offers a unique capacity to accurately link cell death with behavioral dysfunction or phenotypic variation in vivo. Moreover, chemical treatments, as well as forward and reverse genetic screening, hasten the identification of modifiers that alter neurodegeneration. When combined, these chemical-genetic analyses establish critical threshold states to enhance or reduce cellular stress for dissecting associated pathways. Furthermore, C. elegans can rapidly reveal whether lifespan or healthspan factor into neurodegenerative processes. Here, we outline the methodologies employed to investigate neurodegeneration in C. elegans and highlight numerous studies that exemplify its utility as a pre-clinical intermediary to expedite and inform mammalian translational research.

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“…Phosphorylated TFEB was also decreased under C9ORF72-deficient condition, in accordance with increased TFEB nuclear translocation (Ji et al, 2020). On the other hand, there are studies showing the opposite.…”

Section: The C9orf72 Comple X and Mtorc1 S Ig Nalingmentioning

confidence: 68%

“…This phenotype is not further elevated when treated with rapamycin, an inhibitor of mTORC1, indicating that alfa-1 and mTORC1 are in the same pathway in the regulation of HLH-30 (Ji et al, 2020).…”

Section: The C9orf72 Comple X and Mtorc1 S Ig Nalingmentioning

confidence: 96%

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Cellular and physiological functions of C9ORF72 and implications for ALS/FTD

Pang

2020

Journal of Neurochemistry

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The hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the main cause of two tightly linked neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). HRE leads to not only a gain of toxicity from RNA repeats and dipeptide repeats but also reduced levels of C9ORF72 protein. However, the cellular and physiological functions of C9ORF72 were unknown until recently. Through proteomic analysis, Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41) were identified as binding partners of C9ORF72. These three proteins have been shown to form a tight complex, but the exact functions of this complex remain to be characterized. Both C9ORF72 and SMCR8 contain a DENN domain, which has been shown to regulate the activities of small GTPases. The C9ORF72 complex has been implicated in many cellular processes, including vesicle trafficking, lysosome homeostasis, mTORC1 signaling , and autophagy. C9ORF72 deficiency in mice results in exaggerated inflammatory responses and human patients with C9ORF72 mutations have neuroinflammation phenotype. Recent studies indicate that C9ORF72 regulates trafficking and lysosomal degradation of inflammatory mediators, including toll-like receptors (TLRs) and STING, to affect inflammatory outputs. Further exploration of cellular and physiological functions of C9ORF72 will help dissect the pathological mechanism of ALS/ FTD caused by C9ORF72 mutations.

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C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases

Cited by 18 publications

References 64 publications

TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis

TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis

Modeling neurodegeneration in Caenorhabditis elegans

Cellular and physiological functions of C9ORF72 and implications for ALS/FTD

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