Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance

Medina, Diego L.; Fraldi, Alessandro; Bouchè, Valentina; Annunziata, Fabio; Mansueto, Gelsomina; Spampanato, Carmine; Puri, Claudia; Pignata, Antonella; Martina, José A.; Sardiello, Marco; Palmieri, Michela; Polishchuk, Roman; Puertollano, Rosa; Ballabio, Andrea

doi:10.1016/j.devcel.2011.07.016

Cited by 619 publications

(680 citation statements)

References 40 publications

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“…Our data show that oral trehalose administration protects neurons from the pathological accumulation of glycosaminoglycans and that autophagic vacuoles – the putative sites of glycosaminoglycan accumulation – are dramatically cleared from neurons. Thus, if appropriately stimulated, neurons can restore the clearance of intralysosomal material even in the absence of catabolic enzymes, most likely through processes such as lysosomal exocytosis [19]. It is noteworthy that possible therapeutic applications of trehalose may be challenged by the presence of trehalase, a specific trehalose-degrading enzyme, in the intestine, kidney, and other organs in mammals [66].…”

Section: Discussionmentioning

confidence: 99%

“…TFEB (transcription factor EB) is a master regulator of lysosomal pathways, governing lysosomal biogenesis and metabolism [17], autophagy [18], and lysosomal exocytosis [19] and proteostasis [20]. TFEB overexpression promotes lysosomal proliferation and enhances degradative capabilities against lysosomal or autophagic substrates (such as glycosaminoglycans, polyQ-expanded HTT (huntingtin), and ceroid lipopigments), and rescues affected neurons in animal models of proteinopathies [17,21–27].…”

Section: Introductionmentioning

confidence: 99%

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Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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“…Using whole-endolysosome recordings, we recently found that TRPML1 conducts both Ca 2+ and Fe 2+ , and can be activated specifically by PI(3,5)P 2 but not other phosphoinositides (12,16,17). Interestingly, TRPML1 can also be detected in nonlysosome cellular compartments, in particular, the PM, upon exocytosis from the Golgi apparatus (the biosynthetic pathway) (13,14) or the lysosome (lysosomal exocytosis) (18,19). Indeed, when lysosomal exocytosis was dramatically increased by a constitutively active TRPML1 mutant (TRPML1 Va ), large whole-cell TRPML1 currents were detected (18).…”

Section: Trp Channel | Mucolipinmentioning

confidence: 98%

“…The inhibitory effects of the PM-specific phosphoinositides PI (4,5)P 2 , PI(3,4,5)P 3 , and PI(3,4)P 2 , the stimulatory effect of LELspecific PI(3,5)P 2 , and the lack of effect of Golgi-specific PI(4)P or early endosome-specific PI(3)P, indicate that a tight regulatory mechanism controls TRPML1 activity during membrane trafficking. TRPML1 plays a key role in Ca 2+ -dependent lysosomal exocytosis, a cellular process that is important for membrane repair and neurotransmitter release (18,19). Phosphoinositidemediated activation of TRPML1 may lead to lysosomal Ca 2+ release, triggering lysosome exocytosis (17,18).…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide isoforms determine compartment-specific ion channel activity

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

134

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Phosphoinositides serve as address labels for recruiting peripheral cytoplasmic proteins to specific subcellular compartments, and as endogenous factors for modulating the activity of integral membrane proteins. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) is a plasma-membrane (PM)-specific phosphoinositide and a positive cofactor required for the activity of most PM channels and transporters. This requirement for phosphoinositide cofactors has been proposed to prevent PM channel/transporter activity during passage through the biosynthetic/secretory and endocytic pathways. To determine whether intracellularly localized channels are similarly "inactivated" at the PM, we studied PIP 2 modulation of intracellular TRPML1 channels. TRPML1 channels are primarily localized in lysosomes, but can also be detected temporarily in the PM upon lysosomal exocytosis. By directly patch-clamping isolated lysosomes, we previously found that lysosomal, but not PMlocalized, TRPML1 is active with PI(3,5)P 2 , a lysosome-specific PIP 2 , as the underlying positive cofactor. Here we found that "silent" PM-localized TRPML1 could be activated by depleting PI(4,5)P 2 levels and/or by adding PI(3,5)P 2 to inside-out membrane patches. Unlike PM channels, surface-expressed TRPML1 underwent a unique and characteristic run-up upon patch excision, and was potently inhibited by a low micromolar concentration of PI(4,5)P 2 . Conversely, depletion of PI(4,5)P 2 by either depolarization-induced activation or chemically induced translocation of 5′-phosphatase potentiated whole-cell TRPML1 currents. PI(3,5)P 2 activation and PI(4,5)P 2 inhibition of TRPML1 were mediated by distinct basic amino acid residues in a common PIP 2 -interacting domain. Thus, PI(4,5)P 2 may serve as a negative cofactor for intracellular channels such as TRPML1. Based on these results, we propose that phosphoinositide regulation sets compartment-specific activity codes for membrane channels and transporters.TRP channel | mucolipin

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“…ML1-mediated lysosomal Ca 2+ release may regulate many aspects of lysosomal trafficking, including lysosome to trans-Golgi-network (TGN) retrograde trafficking, autophagosome-lysosome fusion, lysosome reformation, and lysosomal exocytosis (15,19,22,23). Moreover, it has been demonstrated that nutrient starvation affects phosphoinositide dynamics and Ca 2+ signaling (16,18,24).…”

Section: Significancementioning

confidence: 99%

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

Wang

Gao

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

192

182

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Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca 2+ channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca 2+ imaging and whole-lysosome patch clamping, lysosomal Ca 2+ release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na + -selective currents were not upregulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca 2+ signaling.

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Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance

Cited by 619 publications

References 40 publications

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Phosphoinositide isoforms determine compartment-specific ion channel activity

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

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