TFEB-mediated increase in peripheral lysosomes regulates store-operated calcium entry

Sbano, Luigi; Bonora, Massimo; Marchi, Saverio; Baldassari, Federica; Medina, Diego L.; Ballabio, Andrea; Giorgi, Carlotta; Pinton, Paolo

doi:10.1038/srep40797

Cited by 42 publications

(34 citation statements)

References 54 publications

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“…Impaired TFEB activity also results in lysosomal-autophagy pathway dysfunction in other neurodegenerative diseases (Martini-Stoica et al 2016). TFEB modulates lysosomal exocytosis, and de-acidification of lysosomes located at the cell periphery is thought to contribute to this process (Medina et al 2011; Sbano et al 2017). A recent study found that HIV infection relocates lysosomes to the periphery of macrophages (Cinti et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Rosario-Rodríguez

Colón

Borges-Vélez

et al. 2018

J Neuroimmune Pharmacol

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HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy, affecting nearly half of HIV-infected patients worldwide. During HIV infection of macrophages secretion of the lysosomal protein, cathepsin B, is increased. Secreted cathepsin B has been shown to induce neurotoxicity. Oxidative stress is increased in HIV-infected patients, while antioxidants are decreased in monocytes from patients with HIV-associated dementia (HAD). Dimethyl fumarate (DMF), an antioxidant, has been reported to decrease HIV replication and neurotoxicity mediated by HIV-infected macrophages. Thus, we hypothesized that DMF will decrease cathepsin B release from HIV-infected macrophages by preventing oxidative stress and enhancing lysosomal function. Monocyte-derived macrophages (MDM) were isolated from healthy donors, inoculated with HIV-1 and treated with DMF following virus removal. After 12 days post-infection, HIV-1 p24 and total cathepsin B levels were measured from HIV-infected MDM supernatants using ELISA; intracellular reactive oxygen and nitrogen species (ROS/RNS) were measured from MDM lysates, and functional lysosomes were assessed using a pH-dependent lysosomal dye. Neurons were incubated with serum-free conditioned media from DMF-treated MDM and neurotoxicity was determined using TUNEL assay. Results indicate that DMF reduced HIV-1 replication and cathepsin B secretion from HIV-infected macrophages in a dose-dependent manner. Also, DMF decreased intracellular ROS/RNS levels, and prevented HIV-induced lysosomal dysfunction and neuronal apoptosis. In conclusion, the improvement in lysosomal function with DMF treatment may represent the possible mechanism to reduce HIV-1 replication and cathepsin B secretion. DMF represents a potential therapeutic strategy against HAND.

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Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Rosario-Rodríguez

Colón

Borges-Vélez

et al. 2018

J Neuroimmune Pharmacol

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“…TFEB controls lysosomal exocytosis inducing local Ca 2+ increase trough the transcriptional activation of the lysosomal cation-channel MCOLN1 and triggering the final fusion of lysosomes with the plasma membrane. Moreover, TFEB regulates lysosomal exocytosis by transcriptionally activating tethering factors and proteins involved in lysosomal dynamics, docking and fusion with the plasma membrane [26]. Therefore, TFEB regulates lysosomal exocytosis by promoting first the lysosome recruitment and docking to the plasma membrane, then the Ca 2+ -mediated fusion event through the activation of the TRPML1 channel.…”

Section: Lysosomal Exocytosismentioning

confidence: 99%

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

Buratta

Tancini

Sagini

et al. 2020

IJMS

285

204

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Beyond the consolidated role in degrading and recycling cellular waste, the autophagic-and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic-and endo-lysosomal systems, evaluating their implication in health and disease.

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“…Notably release of lysosomal Ca 2+ activates calcineurin, which can then dephosphorylate and thus activate TFEB 43 , 44 . TFEB activation has been implicated in regulating lysosomal exocytosis 37 , 45 , by increasing the pool of lysosomes in proximity to the plasma membrane and promoting the fusion of lysosomes with the plasma membrane. In lysosomal storage diseases, lysosomal exocytosis has been described as a beneficial event that relieves the cells from storage material and degradation products 46 , 47 .…”

Section: Discussionmentioning

confidence: 99%

Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons

Magalhaes

Gegg

Migdalska‐Richards

et al. 2018

Sci Rep

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Glucocerebrosidase (GBA1) mutations are the major genetic risk factor for Parkinson’s Disease (PD). The pathogenic mechanism is still unclear, but alterations in lysosomal-autophagy processes are implicated due to reduction of mutated glucocerebrosidase (GCase) in lysosomes. Wild-type GCase activity is also decreased in sporadic PD brains. Small molecule chaperones that increase lysosomal GCase activity have potential to be disease-modifying therapies for GBA1-associated and sporadic PD. Therefore we have used mouse cortical neurons to explore the effects of the chaperone ambroxol. This chaperone increased wild-type GCase mRNA, protein levels and activity, as well as increasing other lysosomal enzymes and LIMP2, the GCase transporter. Transcription factor EB (TFEB), the master regulator of the CLEAR pathway involved in lysosomal biogenesis was also increased upon ambroxol treatment. Moreover, we found macroautophagy flux blocked and exocytosis increased in neurons treated with ambroxol. We suggest that ambroxol is blocking autophagy and driving cargo towards the secretory pathway. Mitochondria content was also found to be increased by ambroxol via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). Our data suggest that ambroxol, besides being a GCase chaperone, also acts on other pathways, such as mitochondria, lysosomal biogenesis, and the secretory pathway.

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TFEB-mediated increase in peripheral lysosomes regulates store-operated calcium entry

Cited by 42 publications

References 54 publications

Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons

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