Discovery and Roles of ER-Endolysosomal Contact Sites in Disease

Henne, William Mike

doi:10.1007/978-981-10-4567-7_10

Cited by 24 publications

(21 citation statements)

References 64 publications

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“…ER-dependent Ca 2+ mobilization, in turn, could stimulate NAADP-induced Ca 2+ release through either local NAADP production or TPC sensitization by cytosolic/intraluminal Ca 2+ (please, note that only TPC1 is sensitive to intraluminal Ca 2+ ) [18]. Ultrastructural analysis revealed that the EL system can be closely (<30 nm) apposed to the ER network [163,164]. As reviewed elsewhere, endosomes-ER MCSs control lipid exchange, cargo sorting, endosome positioning, trafficking and fission [164,165].…”

Section: The Endolysosomal Ca2+ Store: Functions and Mechanisms Ofmentioning

confidence: 99%

“…Ultrastructural analysis revealed that the EL system can be closely (<30 nm) apposed to the ER network [163,164]. As reviewed elsewhere, endosomes-ER MCSs control lipid exchange, cargo sorting, endosome positioning, trafficking and fission [164,165]. Notably, TPC1 favors the formation of these junctional microdomains, thereby promoting the internalization of EGF receptors and curtailing EGF signalling [149,166].…”

Section: The Endolysosomal Ca2+ Store: Functions and Mechanisms Ofmentioning

confidence: 99%

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Endolysosomal Ca2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind!

Faris

Shekha

Montagna

et al. 2018

Cancers

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The acidic vesicles of the endolysosomal (EL) system are emerging as an intracellular Ca2+ store implicated in the regulation of multiple cellular functions. The EL Ca2+ store releases Ca2+ through a variety of Ca2+-permeable channels, including Transient Receptor Potential (TRP) Mucolipin 1-3 (TRPML1-3) and two-pore channels 1-2 (TPC1-2), whereas EL Ca2+ refilling is sustained by the proton gradient across the EL membrane and/or by the endoplasmic reticulum (ER). EL Ca2+ signals may be either spatially restricted to control vesicle trafficking, autophagy and membrane repair or may be amplified into a global Ca2+ signal through the Ca2+-dependent recruitment of ER-embedded channels. Emerging evidence suggested that nicotinic acid adenine dinucleotide phosphate (NAADP)-gated TPCs sustain multiple cancer hallmarks, such as migration, invasiveness and angiogenesis. Herein, we first survey the EL Ca2+ refilling and release mechanisms and then focus on the oncogenic role of EL Ca2+ signaling. While the evidence in favor of TRPML1 involvement in neoplastic transformation is yet to be clearly provided, TPCs are emerging as an alternative target for anticancer therapies.

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Section: The Endolysosomal Ca2+ Store: Functions and Mechanisms Ofmentioning

confidence: 99%

Section: The Endolysosomal Ca2+ Store: Functions and Mechanisms Ofmentioning

confidence: 99%

Endolysosomal Ca2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind!

Faris

Shekha

Montagna

et al. 2018

Cancers

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“…The general importance of ER-endolysosome contacts in HSP is more broadly supported by the recent characterization of 3 additional SPG genes that include spastin (SPG4, a microtubule severing protein), strumpellin (SPG8, involved in recycling of proteins from endosomes) and REEP1 (SPG31, a protein that shapes ER tubules) to have roles at contacts between late endsosomes and the ER (3). In addition to promoting transport of late endosomes and lysosomes, such sites might also serve as sites of lipid transfer to and from the ER (6). Consistent with the importance of such functions, lysosomal lipid accumulation occurs in SPG11 mutant mice (55).…”

Section: Insights Into Neuronal Lysosomes From Human Geneticsmentioning

confidence: 89%

“…Thus, lysosomes do not function in isolation from other organelles but require ongoing delivery of both cargos and hydrolases from the endocytic and autophagic pathways. Lysosomes additionally make contacts with other organelles including the endoplasmic reticulum (ER) (3) and potentially mitochondria (4) that are thought to allow the non-vesicular transfer of lipids and calcium (5,6).…”

mentioning

confidence: 99%

Neuronal lysosomes

Ferguson

2019

Neuroscience Letters

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Lysosomes support diverse cellular functions by acting as sites of macromolecule degradation and nutrient recycling. The degradative abilities of lysosomes are conferred by a lumen that is characterized by an acidic pH and which contains numerous hydrolases that support the breakdown of major cellular macromolecules to yield cellular building blocks (amino acids, nucleic acids, sugars, lipids and metals) that are transported into the cytoplasm for their re-use. In addition to these important hydrolytic and recycling functions, lysosomes also serve as a signaling platform that integrates nutrient and metabolic cues to control signaling via the mTORC1 pathway. Due to their extreme longevity, polarity, demands of neurotransmission and metabolic activity, neurons are particularly sensitive to perturbations in lysosome function. The dependence of neurons on optimal lysosome function is highlighted by insights from human genetics that link lysosome dysfunction to a wide range of both rare and common neurological diseases. How then is lysosome function adapted to the unique demands of neurons? This review will focus on the roles played by lysosomes in distinct neuronal sub-compartments, the regulation of neuronal lysosome sub-cellular localization and the implications of such neuronal lysosome regulation for both physiology and disease.

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“…Interestingly, by the use of a newly developed high-resolution imaging technology Sac1, which has been shown to shuttle between ER and Golgi in response to different stimuli (Blagoveshchenskaya and Mayinger, 2009), has been recently found to reside at the ER-Trans Golgi Network (TGN) contacts sites, where its phosphatase activity controls either ER or Golgi PtdIns4P membrane content (Venditti et al, 2019a,b). ER can establish membrane contacts with TGN as well as with endosomal membranes, referred to as ER-endo-lysosomal contact sites (EELCS) (Eden, 2016; Henne, 2017).…”

Section: Discussionmentioning

confidence: 99%

PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts

et al. 2019

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PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease.

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Discovery and Roles of ER-Endolysosomal Contact Sites in Disease

Cited by 24 publications

References 64 publications

Endolysosomal Ca2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind!

Endolysosomal Ca2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind!

Neuronal lysosomes

PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts

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