A5090743384- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- Autophagy in Disease and Therapy
- Calcium signaling and nucleotide metabolism
- Erythrocyte Function and Pathophysiology
- Metabolism and Genetic Disorders
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Amino Acid Enzymes and Metabolism
- Hippo pathway signaling and YAP/TAZ
- Neonatal Health and Biochemistry
- Biomedical Research and Pathophysiology
- Cell Adhesion Molecules Research
- Autoimmune and Inflammatory Disorders Research
- Nuclear Structure and Function
- NF-κB Signaling Pathways
- Renal and related cancers
- Tuberous Sclerosis Complex Research
- Cytokine Signaling Pathways and Interactions
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Receptor Mechanisms and Signaling
- Renal Diseases and Glomerulopathies
- Vascular Malformations Diagnosis and Treatment
Telethon Institute Of Genetics And Medicine
2017-2025
Istituto Giannina Gaslini
2024
Istituti di Ricovero e Cura a Carattere Scientifico
2024
University of Naples Federico II
2023-2024
Scripps Research Institute
2011-2022
Federico II University Hospital
2022
Institute of Genetics and Biophysics
2002-2010
National Research Council
2005
During starvation the transcriptional activation of catabolic processes is induced by nuclear translocation and consequent transcription factor EB (TFEB), a master modulator autophagy lysosomal biogenesis. However, how TFEB inactivated upon nutrient refeeding currently unknown. Here we show that subcellular localization dynamically controlled its continuous shuttling between cytosol nucleus, with export representing limiting step. mediated CRM1 modulated availability via mTOR-dependent...
A transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports cancer metabolism.
Abstract The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy 1 . phosphorylation by the mechanistic target rapamycin complex (mTORC1) 2–5 unique in its mTORC1 substrate recruitment mechanism, which strictly dependent on amino acid-mediated activation RagC GTPase activating protein FLCN 6,7 lacks TOR signalling motif responsible for other substrates. We used cryogenic-electron microscopy to determine structure as presented phosphorylation, we refer...
Abstract Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) kidney (angiomyolipoma renal cell carcinoma). Previously, we found that TFEB constitutively active TSC. Here, generated two mouse models TSC which pathology the primary phenotype. Knockout rescues overall survival, indicating driver disease Importantly, increased...
Abstract The lysosomal calcium channel TRPML1, whose mutations cause the storage disorder (LSD) mucolipidosis type IV (MLIV), contributes to upregulate autophagic genes by inducing nuclear translocation of transcription factor EB (TFEB). Here we show that TRPML1 activation also induces vesicle (AV) biogenesis through generation phosphatidylinositol 3-phosphate (PI3P) and recruitment essential PI3P-binding proteins nascent phagophore in a TFEB-independent manner. Thus, formation requires...
Abstract Batten disease, one of the most devastating types neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3 . Here, we show that a vesicular trafficking hub connecting Golgi and lysosome compartments. Proteomic analysis reveals interacts with several endo-lysosomal proteins, including cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates targeting enzymes to lysosomes. depletion results mis-trafficking CI-M6PR, mis-sorting enzymes,...
Cytoskeleton remodeling is important for the regulation of vesicular transport associated with exocytosis, but a direct association between granular secretory proteins and actin-remodeling molecules has not been shown, this mechanism remains obscure. Using proteomic approach, we identified RhoA-GTPase-activating protein Gem-interacting (GMIP) as factor that associates Rab27a effector JFC1 modulates exocytosis. GMIP down-regulation induced RhoA activation actin polymerization. Importantly,...
The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation has been associated with pathogenesis several diseases, but role in skeletal disorders largely unknown. Here, we show enhanced signaling arrests bone storage (LSDs). We found dysfunction induces a constitutive...
Cystinosis is a lysosomal storage disorder caused by the accumulation of amino acid cystine due to genetic defects in CTNS gene, which encodes cystinosin, transporter. Although many cellular dysfunctions have been described cystinosis, mechanisms leading these are not well understood. Here, we show that increased overload induced accumulated leads abnormalities, including vesicular transport and endoplasmic reticulum (ER) stress, correction improves function cystinosis. We found Rab27a was...
Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of pathways organized to regulate strength specificity signal transduction events. Ezrin, a membrane-actin linker that assembles coordinates macromolecular at membranes, has recently an important regulator lysosomal function. Here, we report endosomal-localized EGFR/Ezrin complex interacts with triggers inhibition Tuberous Sclerosis Complex (TSC complex) in...
Endosomes have emerged as major signaling hubs where different internalized ligand–receptor complexes are integrated and the outcome of pathways organized to regulate strength specificity signal transduction events. Ezrin, a membrane–actin linker that assembles coordinates macromolecular at membranes, has recently an important regulator lysosomal function. Here, we report endosomal-localized EGFR/Ezrin complex interacts with triggers inhibition Tuberous Sclerosis Complex (TSC complex) in...
Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration dementia in children. In disorders, is preceded severe therapy-resistant autistic-like symptoms unknown cause. Using mouse cellular models MPS-IIIA, we discovered that behaviours are due increased proliferation mesencephalic dopamine neurons originating during embryogenesis, which not dysfunction,...
LPS is an efficient sensitizer of the neutrophil exocytic response to a second stimulus. Although exocytosis in pathogen-derived molecules plays important role innate immune infections, molecular mechanism underlying LPS-dependent regulation currently unknown. The small GTPase Rab27a and its effector Munc13-4 regulate hematopoietic cells. Whether modulate discrete steps or same during also remains Here, using Munc13-4- Rab27a-deficient neutrophils, we analyzed lipopolysaccharide-dependent...
Neutrophils use diverse mechanisms to kill pathogens including phagocytosis, exocytosis, generation of reactive oxygen species (ROS), and neutrophil extracellular traps. These rely on their ability mobilize intracellular organelles deliver granular cargoes specific cellular compartments or into the milieu, but molecular regulating vesicular trafficking in neutrophils are not well understood. MUNC13-4 is a RAB27A effector that coordinates exocytosis hematopoietic cells, its deficiency...
Genetic defects in the Rab27a or Munc13-4 gene lead to immunodeficiencies humans, characterized by frequent viral and bacterial infections. However, role of regulation systemic inflammation initiated Gram-negative bacterium-derived pathogenic molecules is currently unknown. Using a model lipopolysaccharide-induced inflammation, we show that Rab27a-deficient (Rab27a(ash/ash)) mice are resistant lipopolysaccharide (LPS)-induced death, while Munc13-4-deficient (Munc13-4(jinx/jinx)) only...
The molecular mechanisms that regulate late endosomal maturation and function are not completely elucidated, direct evidence of a calcium sensor is lacking. Here we identify novel mechanism involves new interaction between the tethering factor Munc13-4, syntaxin 7, VAMP8. Munc13-4 binding to 7 was significantly increased by calcium. Colocalization at endosomes demonstrated high-resolution live-cell microscopy. Munc13-4-deficient cells show numbers enlarged endosomes, phenotype mimicked...
Abstract Heterozygous mutations in the gene encoding RagD GTPase were shown to cause a novel autosomal dominant condition characterized by kidney tubulopathy and cardiomyopathy. We previously demonstrated that RagD, its paralogue RagC, mediate non-canonical mTORC1 signaling pathway inhibits activity of TFEB TFE3, transcription factors MiT/TFE family master regulators lysosomal biogenesis autophagy. Here we show causing cardiomyopathy are “auto- activating”, even absence Folliculin, GAP...
Abstract Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of formylglycine‐generating enzyme (FGE). FGE is essential for posttranslational activation cellular sulfatases. MSD patients display reduced or absent activities and, as a result, clinical signs single disorders unique combination. Up to date therapeutic options are limited and mostly palliative. We performed screen FDA‐approved drugs using immortalized...
The Arp2/3 complex is essential for actin filament nucleation in a variety of cellular processes. activation the mediated by nucleation-promoting factors, such as Wiskott-Aldrich syndrome family proteins, which share WCA (WH2 domain, central region, acidic region) catalytic module at C-terminal required activation, but diverge N-terminal binding to specific activators. Here, we report characterization WASH, new member WAS that has factor activity and recently been demonstrated play role...