Solutes as controllers of endomembrane dynamics

Sarić, Amra; Freeman, Spencer A.

doi:10.1038/s41580-021-00334-0

Cited by 11 publications

(11 citation statements)

References 9 publications

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“…In addition to initiating endomembrane remodeling events 40 , the efflux of luminal solutes is an important requirement for lysosomal transport 41 . Therefore, we next asked whether the morphological disturbances observed in Slc37a2 KO SLs altered their capacity to translocate to the osteoclast-ruffled border.…”

Section: Resultsmentioning

confidence: 99%

Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts

Ribet

Guo

et al. 2023

Nat Commun

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Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate in mice that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the bone-lining osteoclast plasma membrane. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases.

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Section: Resultsmentioning

confidence: 99%

Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts

Ribet

Guo

et al. 2023

Nat Commun

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“…In addition to initiating endomembrane remodeling events (Saric and Freeman, 2021), the efflux of luminal solutes is an important requirement for lysosomal transport (Bandyopadhyay et al, 2014). Therefore, we next asked whether the morphological disturbances observed in Slc37a2 KO SLs altered their capacity to translocate to the osteoclast ruffled border.…”

Section: Resultsmentioning

confidence: 99%

Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts

Ribet

Guo

et al. 2022

Preprint

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Osteoclasts are giant bone-digesting cells that harbour specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the ruffled border. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases.

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“…Macropinosome shrinkage is therefore largely mediated by Na + flux across the vesicle membrane. Recent studies demonstrated that Na + efflux down its gradient from the pinosome to the cytosol is controlled by the non-selective TRPML cation channels and TPC Na + channels ( Laplante et al, 2002 ; Freeman et al, 2020 ; Chadwick et al, 2021a , b ; Saric and Freeman, 2021 ).…”

Section: Vesicular Volume Regulationmentioning

confidence: 99%

“…Also, proteins of the ESCRT complexes take advantage of the slack membrane to induce inwardly budding intraluminal vesicles (ILVs) and further on MVBs. Thus, the vesicular shrinkage creates organelles with high surface-to-volume ratios, relieves the hydrostatic tension of their membranes, and is hence critical for their resolution (for review, see Freeman and Grinstein, 2018 ; Chen et al, 2020b ; Saric and Freeman, 2020 , 2021 ; Chadwick et al, 2021a , b ).…”

Section: Vesicular Volume Regulationmentioning

confidence: 99%

“…Recent studies indicate that volume regulation in cells and cell organelles is governed by the same biophysical principles and by the overlapping use of ion channels and transporters in distinct cellular compartments ( Saric and Freeman, 2020 , 2021 ; Chadwick et al, 2021a , b ). That is, it starts with the asymmetric distribution of ions and materializes in the well-orchestrated uptake and processing of engulfed material in specialized vesicles ( Chadwick et al, 2021a ).…”

Section: Perspectivesmentioning

confidence: 99%

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From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

Ritter

Bresgen

Kerschbaum

2021

Front. Cell Dev. Biol.

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The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell’s surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and—most importantly—shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement.

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Solutes as controllers of endomembrane dynamics

Cited by 11 publications

References 9 publications

Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts

Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts

Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

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