![]() ![]() A resource for generating and manipulating human microglial states in vitro. microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Genome-wide association study identified ATP6V1H locus influencing cerebrospinal fluid BACE activity. v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Deficiency of ATP6V1H causes bone loss by inhibiting bone resorption and bone formation through the TGF-β1 pathway. Subunit H of the vacuolar (H+) ATPase inhibits ATP hydrolysis by the free V1 domain by interaction with the rotary subunit F. VMA13 encodes a 54-kDa vacuolar H(+)-ATPase subunit required for activity but not assembly of the enzyme complex in Saccharomyces cerevisiae. Regulation and isoform function of the V-ATPases. Emerging roles for TFEB in the immune response and inflammation. TFEB and TFE3 are novel components of the integrated stress response. The autophagy-lysosomal pathway in neurodegeneration: a TFEB perspective. Degradable nanoparticles restore lysosomal pH and autophagic flux in lipotoxic pancreatic beta cells. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. The TREM2-APOEpathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. A unique microglia type associated with restricting development of Alzheimer’s disease. A seeding based cellular assay of tauopathy. Mitf is a master regulator of the v-ATPase, forming a control module for cellular homeostasis with v-ATPase and TORC1. Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading. Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing Aβgeneration and amyloid plaque pathogenesis. Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-β precursor protein. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. TFEB links autophagy to lysosomal biogenesis. A gene network regulating lysosomal biogenesis and function. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Disorders of lysosomal acidification-the emerging role of v-ATPase in aging and neurodegenerative disease. Lysosomes as dynamic regulators of cell and organismal homeostasis. Our studies demonstrate a physiological function of TFEB–v-ATPase signaling in maintaining lysosomal homeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer’s disease.īallabio, A. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and were locked in a homeostatic state. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. To explore the lysosome–immune relationship, we specifically disrupted the TFEB–v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. Single-nucleus RNA sequencing of wild-type and PS19 (Tau) transgenic mice expressing the P301S mutant tau identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. TFEB targets include subunits of the vacuolar ATPase (v-ATPase), which are essential for lysosome acidification. Transcription factor EB (TFEB) mediates gene expression through binding to the coordinated lysosome expression and regulation (CLEAR) sequence. ![]()
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