Редактирование: TFEB

Transcription factor EB (Class E basic helix-loop-helix protein 35) (bHLHe35) [BHLHE35]

==Publications==

{{medline-entry
|title=A Novel Lipofuscin-detecting Marker of Senescence Relates With Hypoxia, Dysregulated Autophagy and With Poor Prognosis in Non-small-cell-lung Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33144423
|abstract=The role of senescence in defining tumor aggressiveness at a clinical level remains obscure. A novel mixed histochemical/immunohistochemical method (SenTraGor™, STG) detecting lipofuscin accumulation allows the assessment of senescent cells in paraffin-embedded tissue material. STG expression was quantified in 98 surgically resected primary non-small-cell-lung carcinomas (NSCLC). Data were analyzed in parallel with other immunohistochemical markers related to hypoxia and autophagy. Strong STG staining was noted in 36/98 cases (36.7%). High STG expression was significantly associated with high HIF1α expression and high expression of glucose (GLUT1) and monocarboxylate (MCT2) transporters, pointing to a link between senescence, hypoxia and glycolysis. High STG expression was also linked with high cytoplasmic accumulation of MAP1-LC3B, [[TFEB]] and LAMP2a, suggestive of a blockage of autophagy flux in tumors with intense senescence. Survival analysis showed a direct association with poor survival, independently of stage. SenTraGor™ provides a reliable methodology to detect lipofuscin accumulation in cancer cells in paraffin-embedded tissues, opening a new field for translational studies focused on senescence.

|keywords=* Senescence
* autophagy
* glycolysis
* hypoxia
* lipofuscin
* lung cancer
|full-text-url=https://sci-hub.do/10.21873/invivo.12154
}}
{{medline-entry
|title=ESC-sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32440476
|abstract=Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time-related increasing in hippocampal neural stem cells (H-NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell-derived small extracellular vesicles (ESC-sEVs) are intravenously injected into VD rats. ESC-sEVs treatment significantly alleviates H-NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT-qPCR it is identified that several miRNAs including miR-17-5p, miR-18a-5p, miR-21-5p, miR-29a-3p, and let-7a-5p, that can inhibit mTORC1 activation, exist in ESC-sEVs. ESC-sEVs rejuvenate H-NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB ([[TFEB]]) nuclear translocation and lysosome resumption. Taken together, these data indicate that H-NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC-sEVs treatment ameliorates H-NSCs senescence by inhibiting mTORC1 activation, and promoting [[TFEB]] nuclear translocation and lysosome resumption, thereby reversing senescence-related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC-sEVs may be a novel cell-free therapeutic tool for patients with VD, as well as other aging-related diseases.

|keywords=* embryonic stem cells derived small extracellular vesicles (ESC‐sEVs)
* hippocampal neural stem cells (HNSCs)
* lysosomes
* senescence
* vascular dementia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237844
}}
{{medline-entry
|title=Nitrative Stress-Related Autophagic Insufficiency Participates in Hyperhomocysteinemia-Induced Renal Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32047576
|abstract=The kidneys are important organs that are susceptible to aging. Hyperhomocysteinemia (HHcy) is a risk factor for nephropathy and is associated with chronic nephritis, purpuric nephritis, and nephrotic syndrome. Numerous studies have shown that elevated serum homocysteine levels can damage the kidneys; however, the underlying mechanism of HHcy on kidney damage remains unclear. In this study, we make use of a diet-induced HHcy rat model and in vitro cell culture to explore the role of autophagy in HHcy-induced renal aging and further explored the underlying mechanism. We demonstrated that HHcy led to the development of renal aging. Promoted kidney aging and autophagic insufficiency were involved in HHcy-induced renal aging. HHcy decreased the expression of transcription factor EB ([[TFEB]]), the key transcription factor of autophagy-related genes in renal tissue. Further experiments showed that nitrative stress levels were increased in the kidney of HHcy rats. Interestingly, pretreatment with the peroxynitrite (ONOO ) scavenger FeTMPyP not only reduced the Hcy-induced nitrative stress in vitro but also partially attenuated the decrease in [[TFEB]] in both protein and mRNA levels. Moreover, our results indicated that HHcy reduced [[TFEB]] expression and inhibited [[TFEB]]-mediated autophagy activation by elevating nitrative stress. In conclusion, this study showed an important role of autophagic insufficiency in HHcy-induced renal aging, in which downregulation of [[TFEB]] plays a major role. Furthermore, downexpression of [[TFEB]] was associated with increased nitrative stress in HHcy. This study provides a novel insight into the mechanism and therapeutic strategy for renal aging.
|mesh-terms=* Aging
* Animals
* Autophagy
* Cells, Cultured
* Homocysteine
* Humans
* Hyperhomocysteinemia
* Kidney
* Kidney Diseases
* Male
* Metalloporphyrins
* Peroxynitrous Acid
* Rats
* Rats, Sprague-Dawley

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007752
}}
{{medline-entry
|title=Polyamines reverse immune senescence via the translational control of autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31679458
|abstract=Organismal aging is associated with compromised cellular function, which can be partially attributed to accumulation of cellular damage. Being the major, if not only, cellular bulk-degradation mechanism, macroautophagy (hereafter autophagy) declines with age in multiple tissues and organisms. Spermidine is an endogenous polyamine metabolite that also declines with age. It prolongs lifespan and improves tissue functions of model organisms in an autophagy-dependent manner. We report that autophagic flux is significantly reduced in B cells from old mice. Spermidine induces autophagy and improves the function of both old mouse and old human B cells. Mechanistically, spermidine post-translationally modifies (hypusinates) the translation factor [[EIF5A]]. Hypusinated [[EIF5A]] specifically regulates the synthesis of the master autophagy and lysosome transcription factor, [[TFEB]] (transcription factor EB). This pathway declines with age in both mice and humans, which may eventually lead to declining autophagy and impaired tissue functions in old individuals.
|mesh-terms=* Aging
* Animals
* Autophagy
* Humans
* Lysosomes
* Polyamines
* Protein Processing, Post-Translational
* Spermidine
|keywords=* Aging
* B cells
* EIF5A
* TFEB
* autophagy
* hypusine
* spermidine
* translation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984486
}}
{{medline-entry
|title=[[MAP4K3]]/GLK in autoimmune disease, cancer and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31640697
|abstract=[[MAP4K3]] (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor [[TFEB]] and retains [[TFEB]] in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKCθ through phosphorylating PKCθ at Ser-538 residue, leading to activation of IKK/NF-κB. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORγt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates [[IQGAP1]], resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting [[MAP4K3]] (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
|mesh-terms=* Aging
* Autoimmune Diseases
* Humans
* Neoplasms
* Protein-Serine-Threonine Kinases
|keywords=* Aging
* Autoimmune disease
* Autophagy
* Cancer metastasis
* HPK1
* IL-17A
* IQGAP1
* MAP4K3 (GLK)
* PKCθ
* Verteporfin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806545
}}
{{medline-entry
|title=Pleiotropic Effects of mTOR and Autophagy During Development and Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31572724
|abstract=Autophagy as a ubiquitous catabolic process causes degradation of cytoplasmic components and is generally considered to have beneficial effects on health and lifespan. In contrast, inefficient autophagy has been linked with detrimental effects on the organism and various diseases, such as Parkinson's disease. Previous research, however, showed that this paradigm is far from being black and white. For instance, it has been reported that increased levels of autophagy during development can be harmful, but become advantageous in the aging cell or organism, causing enhanced healthspan and even longevity. The antagonistic pleiotropy hypothesis postulates that genes, which control various traits in an organism, can be fitness-promoting in early life, but subsequently trigger aging processes later. Autophagy is controlled by the mechanistic target of rapamycin (mTOR), a key player of nutrient sensing and signaling and classic example of a pleiotropic gene. mTOR acts upstream of transcription factors such as FOXO, NRF, and [[TFEB]], controlling protein synthesis, degradation, and cellular growth, thereby regulating fertility as well as aging. Here, we review recent findings about the pleiotropic role of autophagy during development and aging, examine the upstream factors, and contemplate specific mechanisms leading to disease, especially neurodegeneration.

|keywords=* C. elegans
* aging
* autophagy
* genetics
* pleiotropy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749033
}}
{{medline-entry
|title=Polyamines Control eIF5A Hypusination, [[TFEB]] Translation, and Autophagy to Reverse B Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31474573
|abstract=Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor [[TFEB]]. Spermidine is depleted in the elderly, leading to reduced [[TFEB]] expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.
|mesh-terms=* Adaptive Immunity
* Age Factors
* Aging
* Animals
* Autophagy
* B-Lymphocytes
* Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
* Cellular Senescence
* HEK293 Cells
* Humans
* Immunologic Memory
* Immunosenescence
* Jurkat Cells
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* NIH 3T3 Cells
* Peptide Initiation Factors
* Protein Processing, Post-Translational
* RNA-Binding Proteins
* Signal Transduction
* Spermidine
|keywords=* B cell
* TFEB
* aging
* autophagy
* eIF5A
* spermidine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863385
}}
{{medline-entry
|title=Insulin-like peptides and the mTOR-[[TFEB]] pathway protect [i]Caenorhabditis elegans[/i] hermaphrodites from mating-induced death.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31282862
|abstract=Lifespan is shortened by mating, but these deleterious effects must be delayed long enough for successful reproduction. Susceptibility to brief mating-induced death is caused by the loss of protection upon self-sperm depletion. Self-sperm maintains the expression of a DAF-2 insulin-like antagonist, [[INS]]-37, which promotes the nuclear localization of intestinal HLH-30/[[TFEB]], a key pro-longevity regulator. Mating induces the agonist [[INS]]-8, promoting HLH-30 nuclear exit and subsequent death. In opposition to the protective role of HLH-30 and DAF-16/FOXO, TOR/LET-363 and the IIS-regulated Zn-finger transcription factor PQM-1 promote seminal-fluid-induced killing. Self-sperm maintenance of nuclear HLH-30/[[TFEB]] allows hermaphrodites to resist mating-induced death until self-sperm are exhausted, increasing the chances that mothers will survive through reproduction. Mothers combat males' hijacking of their IIS pathway by expressing an insulin antagonist that keeps her healthy through the activity of pro-longevity factors, as long as she has her own sperm to utilize.
|mesh-terms=* Animals
* Basic Helix-Loop-Helix Transcription Factors
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Disorders of Sex Development
* Female
* Insulin
* Longevity
* Male
* Peptides
* Reproduction
* Sexual Behavior, Animal
* Signal Transduction
* TOR Serine-Threonine Kinases
|keywords=* C. elegans
* TFEB
* genetics
* genomics
* insulin signaling
* lifespan
* mTOR
* mating
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697448
}}
{{medline-entry
|title=Double knockout of Akt2 and AMPK predisposes cardiac aging without affecting lifespan: Role of autophagy and mitophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31109453
|abstract=Increased age often leads to a gradual deterioration in cardiac geometry and contractile function although the precise mechanism remains elusive. Both Akt and AMPK play an essential role in the maintenance of cardiac homeostasis. This study examined the impact of ablation of Akt2 (the main cardiac isoform of Akt) and AMPKα2 on development of cardiac aging and the potential mechanisms involved with a focus on autophagy. Cardiac geometry, contractile, and intracellular Ca  properties were evaluated in young (4-month-old) and old (12-month-old) wild-type (WT) and Akt2-AMPK double knockout mice using echocardiography, IonOptix® edge-detection and fura-2 techniques. Levels of autophagy and mitophagy were evaluated using western blot. Our results revealed that increased age (12 months) did not elicit any notable effects on cardiac geometry, contractile function, morphology, ultrastructure, autophagy and mitophagy, although Akt2-AMPK double knockout predisposed aging-related unfavorable changes in geometry (heart weight, LVESD, LVEDD, cross-sectional area and interstitial fibrosis), TEM ultrastructure, and function (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, intracellular Ca  release and clearance rate). Double knockout of Akt2 and AMPK unmasked age-induced cardiac autophagy loss including decreased Atg5, Atg7, Beclin1, LC3BII-to-LC3BI ratio and increased p62. Double knockout of Akt2 and AMPK also unmasked age-related loss in mitophagy markers [[PTEN]]-induced putative kinase 1 (Pink1), Parkin, Bnip3, and FundC1, the mitochondrial biogenesis cofactor [[PGC]]-1α, and lysosomal biogenesis factor [[TFEB]]. In conclusion, our data indicate that Akt2-AMPK double ablation predisposes cardiac aging possibly related to compromised autophagy and mitophagy. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren