A cation counterflux supports lysosomal acidification

Steinberg, Benjamin E.; Huynh, Kassidy K.; Brodovitch, Alexandre; Jabs, Sabrina; Stauber, Tobias; Jentsch, Thomas J.; Grinstein, Sergio

doi:10.1083/jcb.200911083

Cited by 256 publications

(286 citation statements)

References 40 publications

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“…Without ClC-7/Ostm1 to operate alongside the V-ATPase to dissipate the transmembrane electrical potential difference, osteoclasts fail to acidify the extracellular resorption lacuna (Kornak et al, 2001). Lysosomal pH, on the other hand, is normal in cells lacking ClC-7/Ostm1 due to shunting provided by cation counterflux (Kasper et al, 2005; Steinberg et al, 2010). Knock-in mice, Clcn7 unc/unc , in which ClC-7 Cl − /H + exchange is converted to chloride channel, also display osteopetrosis (albeit milder) and lysosomal pathology, indicating that Cl − /H + exchanging activity mediated by ClC-7, rather than Cl − conductance alone, is critical for osteoclast and lysosomal function (Weinert et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

Wen

Lacruz

Paine

2015

The Anatomical Record

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ClC-7 is a 2Cl−/1H+-exchanger expressed at late endosomes and lysosomes, as well as the ruffled border of osteoclasts. ClC-7 deficiencies in mice and humans lead to impaired osteoclast function and therefore osteopetrosis. Failure of tooth eruption is also apparent in ClC-7 mutant animals, and this has been attributed to the osteoclast dysfunction and the subsequent defect in alveolar bone resorptive activity surrounding tooth roots. Ameloblasts also express ClC-7, and this study aims to determine the significance of ClC-7 in enamel formation by examining the dentitions of ClC-7 mutant mice. Micro-CT analysis revealed that the molar teeth of 3-week old ClC-7 mutant mice had no roots, and the incisors were smaller than their age-matched controls. Despite these notable developmental differences, the enamel and dentin densities of the mutant mice were comparable to those of the wild type littermates. Scanning electron microscopy (SEM) showed normal enamel crystallite and prismatic organization in the ClC-7 mutant mice, although the enamel was thinner (hypoplastic) than in controls. These results suggested that ClC-7 was not critical to enamel and dentin formation, and the observed tooth defects may be related more to a resulting alveolar bone phenotype. Micro-CT analysis also revealed abnormal features in the calvarial bones of the mutant mice. The cranial sutures in ClC-7 mutant mice remained open compared to the closed sutures seen in the control mice at 3 weeks. These data demonstrate that ClC-7 deficiency impacts the development of the dentition and calvaria, but does not significantly disrupt amelogenesis.

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Section: Discussionmentioning

confidence: 99%

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

Wen

Lacruz

Paine

2015

The Anatomical Record

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“…Therefore, the loss of Nhx1p activity resulted in a shift in intracellular sodium, potassium, and proton concentrations. However, Nhx1p activity does not noticeably change endosomal or cytosolic Na ϩ and K ϩ concentrations, because of the much higher concentration of Na ϩ or K ϩ than H ϩ in cells (46,47). Thus, we considered the potential importance of pH in MVB formation.…”

Section: Discussionmentioning

confidence: 99%

The Endosomal Na+/H+ Exchanger Contributes to Multivesicular Body Formation by Regulating the Recruitment of ESCRT-0 Vps27p to the Endosomal Membrane

Mitsui

Koshimura

Yoshikawa

et al. 2011

Journal of Biological Chemistry

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Multivesicular bodies (MVBs) are late endosomal compartments containing luminal vesicles (MVB vesicles) that are formed by inward budding of the endosomal membrane. In budding yeast, MVBs are an important cellular mechanism for the transport of membrane proteins to the vacuolar lumen. This process requires a class E subset of vacuolar protein sorting (VPS) genes. VPS44 (allelic to NHX1) encodes an endosomelocalized Na ؉ /H ؉ exchanger. The function of the VPS44 exchanger in the context of vacuolar protein transport is largely unknown. Using a cell-free MVB formation assay system, we demonstrated that Nhx1p is required for the efficient formation of MVB vesicles in the late endosome. The recruitment of Vps27p, a class E Vps protein, to the endosomal membrane was dependent on Nhx1p activity and was enhanced by an acidic pH at the endosomal surface. Taken together, we propose that Nhx1p contributes to MVB formation by the recruitment of Vps27p to the endosomal membrane, possibly through Nhx1p antiporter activity.Multivesicular bodies (MVBs) 3 are a subset of late endosomes that contain internal vesicles, permitting precursor and plasma membrane proteins to reach the lysosome or vacuole lumen for degradation or maturation, respectively. In eukaryotic cells, the MVB pathway controls various important processes such as receptor down-regulation, antigen presentation, cytokinesis, retroviral budding, and autophagy (1-6). In the budding yeast Saccharomyces cerevisiae, previous studies identified a number of genes involved in vacuolar protein sorting (VPS) (7,8). These Vps proteins function at distinct steps of protein transport between the Golgi complex and the vacuole (7,8). A subset of Vps proteins, class E proteins, is involved in MVB formation. Most class E proteins are components of five distinct complexes; Vps27p-Hse1p (also called endosomal sorting complexes required for transport-0 (ESCRT-0), -I, -II, and -III and Vps4p. These complexes are required for the formation of internal vesicles and sorting of cargo proteins to the vesicles from the endosomal membrane (3, 9). Vps27p (ESCRT-0) recruits ESCRT-I, which in turn recruits and/or activates ESCRT-II and ESCRT-III at the endosome (3, 10). Recent in vitro studies have provided new insights into the precise role of each ESCRT complex in MVB formation (11-13). ESCRT-0 initiates the MVB sorting process by recruiting ESCRT-I to the endosomal membrane and concentrating ubiquitylated MVB cargos to the vesicle budding site (12). ESCRT-I and ESCRT-II are directly involved in membrane budding by stabilizing the bud necks, whereas ESCRT-III is responsible for the cleavage of bud necks (11-13). Finally, the AAA-type ATPase Vps4p dissociates the ESCRT-III complex from the endosome (14). The sequential activity of these complexes on the cytoplasmic surface of endosomes directs the budding and fission of vesicles into the lumen of the endosome and the sequestration of cargo proteins in the vesicle. Defects in ESCRT proteins prevent internal vesicle formation and result in exagg...

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“…The physiological sodium concentration applied here (140 mM) is characteristic to the extracellular space. However, intracellular organelles such as lysosomes are featured with lower cationic content, ~60 mM Na + and ~20 mM K + , 20 that is very close to the ionic strength used in the present study (80-100 mM Na + , see Table 1). Importantly, catabolism of GAGs is intimately related to lysosomes 21 and pentamidine was shown to be selectively accumulated in these subcellular compartments.…”

Section: Resultsmentioning

confidence: 93%

Glycosaminoglycans are potential pharmacological targets for classic DNA minor groove binder drugs berenil and pentamidine

Zsila

2015

Phys. Chem. Chem. Phys.

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It is shown that the antiprotozoal berenil and pentamidine, conventional minor groove binders of DNA, form non-covalent complexes with polyanionic glycosaminoglycans. Induced circular dichroism (CD) spectra as well as UV hypochromism confirmed drug binding to the asymmetric template of heparin and chondroitin 6-sulfate. The biphasic nature of the CD signals refer to intermolecular chiral exciton coupling between the dicationic guest molecules forming a right-or a left-handed helical array along the GAG chains. Quantitative evaluation of the spectroscopic data measured in pH 7.0 buffer solution (80 mM NaCl) indicated a high-(K a ~ 10 6 M -1 for berenil) and a lower (K a ~ 10 5 M -1 for pentamidine) affinity heparin binding of these agents, similar to that reported for DNA. Drug-chondroitin sulfate complexes (K a ~ 10 4 -10 5 M -1 ) could only be detected at low ionic strength. These results imply that besides nucleic acids, GAGs may be another pharmacological target for diarylamidine drugs.

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A cation counterflux supports lysosomal acidification

Abstract: Lysosomes lose cations to balance the influx of protons as the organelle acidifies.

Cited by 256 publications

References 40 publications

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

The Endosomal Na+/H+ Exchanger Contributes to Multivesicular Body Formation by Regulating the Recruitment of ESCRT-0 Vps27p to the Endosomal Membrane

Glycosaminoglycans are potential pharmacological targets for classic DNA minor groove binder drugs berenil and pentamidine

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A cation counterflux supports lysosomal acidification

Abstract: Lysosomes lose cations to balance the influx of protons as the organelle acidifies.

Cited by 256 publications

References 40 publications

Dental and Cranial Pathologies in Mice Lacking the Cl−/H+‐Exchanger ClC‐7

Dental and Cranial Pathologies in Mice Lacking the Cl−/H+‐Exchanger ClC‐7

The Endosomal Na+/H+ Exchanger Contributes to Multivesicular Body Formation by Regulating the Recruitment of ESCRT-0 Vps27p to the Endosomal Membrane

Glycosaminoglycans are potential pharmacological targets for classic DNA minor groove binder drugs berenil and pentamidine

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Product

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Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7