Stomatin (STOM): A Comprehensive Research Report

1. Introduction

Stomatin (STOM), also known as erythrocyte band 7 integral membrane protein or protein 7.2b, is a 31.5 kDa monotopic membrane protein belonging to the evolutionarily ancient band 7/mec-2 family [hiebl-dirschmied-1991-cloning-abstract]. First identified as a major component of the human erythrocyte membrane, stomatin is characterized by the presence of a conserved SPFH (stomatin/prohibitin/flotillin/HflK/C) domain, also referred to as the band 7 or prohibitin homology (PHB) domain. The protein was named after hereditary stomatocytosis, a hemolytic anemia in which stomatin is notably absent from red blood cell membranes, though paradoxically no mutations in the STOM gene itself have been found in this condition [fricke-2005-ohst-trafficking-abstract].

Stomatin functions primarily as a membrane-organizing scaffolding protein that regulates the activity of multiple ion channels and membrane transporters through direct protein-protein interactions. The protein associates with cholesterol-rich lipid rafts, forms higher-order oligomeric structures, and recruits its target proteins to these specialized membrane domains [rungaldier-2017-stomatin-structure-function-abstract]. Beyond its well-established roles in transport regulation, recent research has revealed unexpected functions in cell division, lipid metabolism, and innate immunity. This review synthesizes current understanding of stomatin's molecular function, subcellular localization, structural features, and roles in physiological and pathological contexts, with particular emphasis on its conserved role in regulating mechanosensation through ion channel modulation.

2. Protein Structure and Membrane Topology

2.1 Domain Organization

Human stomatin is encoded by the STOM gene and consists of 287 amino acids. The protein contains several functionally important regions: an N-terminal membrane-anchoring domain, a central SPFH/band 7 domain (also called the stomatin domain), and a C-terminal coiled-coil domain essential for oligomerization [hiebl-dirschmied-1991-cloning-abstract]. The SPFH domain spans approximately residues 86-213 in mouse stomatin and adopts a mixed α/β-fold similar to other SPFH family members [brand-2012-stomatin-dimer-abstract].

2.2 Unique Hairpin-Loop Membrane Topology

Unlike typical transmembrane proteins, stomatin adopts a distinctive monotopic membrane topology characterized by a hydrophobic hairpin-loop structure. In this configuration, a short hydrophobic stretch of approximately 29 residues near the N-terminus inserts into the membrane but does not traverse it completely, leaving both the N- and C-termini exposed to the cytoplasm [kadurin-2009-proline-topology-abstract]. This topology is critically dependent on a highly conserved proline residue (Pro-47) located in the middle of the hydrophobic domain. When this proline is mutated to serine, the entire stomatin pool adopts a single-pass transmembrane configuration and loses its ability to localize to detergent-resistant membrane domains (lipid rafts), demonstrating that the hairpin-loop formation is inefficient and requires this conserved proline residue [kadurin-2009-proline-topology-abstract].

2.3 Post-Translational Modifications

Stomatin undergoes palmitoylation at multiple cysteine residues, particularly Cys-30 and Cys-87. Palmitoylation of Cys-87 is essential for attachment of the SPFH domain to the plasma membrane, while Cys-30 resides within the intramembrane domain and provides additional membrane anchoring [rungaldier-2017-stomatin-structure-function-abstract]. These post-translational modifications, combined with the hydrophobic hairpin structure, result in a biochemical profile similar to caveolins and other integral scaffolding proteins.

2.4 Crystal Structure and Oligomerization

Crystallographic studies of the mouse stomatin SPFH domain revealed that the basic building block is a "banana-shaped dimer" formed through an intermolecular β-sheet at the C-terminus of the stomatin domain, burying approximately 600 Ų of surface area per molecule [brand-2012-stomatin-dimer-abstract]. This dimerization is functionally critical; disrupting the dimer interface through the V197P mutation abolishes stomatin's ability to modulate acid-sensing ion channels (ASICs). Beyond dimers, stomatin assembles into ring-like cylindrical oligomers with an outer diameter of approximately 8 nm, representing higher-order structures built from banana-shaped dimeric building blocks [brand-2012-stomatin-dimer-abstract]. The coiled-coil domain at the C-terminus is essential for this oligomerization, and association with cholesterol-rich membranes appears to be a prerequisite for oligomer formation [rungaldier-2017-stomatin-structure-function-abstract].

A crucial functional element identified in the crystal structure is a hydrophobic pocket at the concave face of the stomatin dimer, with a volume of approximately 350 ų. This pocket can accommodate small hydrophobic peptides and exhibits dynamic open-closed behavior. Mutation of this pocket (T182W) eliminated stomatin's inhibitory function on ASIC3 and ASIC2a channels despite maintaining proper protein folding and localization, establishing the hydrophobic pocket as essential for ion channel regulation [brand-2012-stomatin-dimer-abstract].

3. Subcellular Localization

3.1 Lipid Raft Association

Stomatin is primarily localized to cholesterol-rich membrane microdomains known as lipid rafts. In erythrocytes, along with flotillin-1 and flotillin-2, stomatin is among the most abundant integral proteins of lipid raft fractions isolated by detergent resistance assays [mairhofer-2002-platelet-abstract]. Stomatin has been identified as a cholesterol-binding protein, with two domains important for cholesterol-rich membrane association: the CRAC/CARC domain (residues 55-68) and the ORA/CARC domain (residues 263-273). Both domains contribute equally to lipid raft localization [rungaldier-2017-stomatin-structure-function-abstract]. A highly conserved proline residue in the hydrophobic domain has also been proposed to directly bind cholesterol and is necessary for ion channel regulation [kadurin-2009-proline-topology-abstract].

3.2 Distribution Across Cell Types

While initially characterized in erythrocytes, stomatin is widely expressed across many tissues and cell types. Expression has been documented in visceral pleura, pericardium, vena cava, and over 200 other cell types and tissues. Beyond the plasma membrane, stomatin localizes to specific subcellular compartments depending on cell type. In platelets, stomatin is found predominantly at the α-granular membrane rather than the plasma membrane. Upon platelet activation by calcium ionophore or thrombin, stomatin translocates to the plasma membrane, undergoes calpain-mediated cleavage, and is sorted into released microvesicles, suggesting a role in α-granule organization and function [mairhofer-2002-platelet-abstract].

Stomatin-carrying endosomes have been observed to be highly dynamic and interact with lipid droplets, suggesting potential roles in intracellular lipid transport. In sensory neurons, stomatin and its homologs localize along neuronal processes, particularly in mechanosensory cells where they form complexes with ion channels [huang-1995-mec2-abstract].

4. Molecular Function: Ion Channel and Transporter Regulation

4.1 Modulation of Acid-Sensing Ion Channels (ASICs)

One of the best-characterized functions of stomatin is its modulation of acid-sensing ion channels (ASICs), proton-gated sodium channels involved in sensory neuron function. Stomatin co-immunoprecipitates and co-localizes with ASIC proteins in heterologous cells, and functionally alters their gating properties [price-2004-stomatin-asic-abstract].

The effects of stomatin differ depending on the ASIC subtype. For ASIC3, stomatin potently reduces acid-evoked currents without affecting steady-state protein levels or surface expression, indicating a direct effect on channel gating or conductance. For ASIC2a and heteromeric ASICs, stomatin accelerates the desensitization rate without affecting current amplitude. Detailed mechanistic studies identified that regulation requires two distinct sites on ASIC3: the distal C-terminus (containing a di-leucine motif at positions 488-489) that is critical for formation of the stomatin-ASIC3 complex, and the first transmembrane domain (TM1) that is required only for the regulatory effect [price-2004-stomatin-asic-abstract, brand-2012-stomatin-dimer-abstract].

4.2 Regulation of Glucose Transporter GLUT1

Stomatin directly associates with and modulates the glucose transporter GLUT1, one of the most abundant proteins in human erythrocytes. Co-immunoprecipitation experiments demonstrated that stomatin specifically interacts with GLUT1 through its C-terminal 42-amino acid segment, while neither band 3 (the most abundant erythrocyte membrane protein) nor actin showed similar interaction patterns, indicating specificity [zhang-1999-stomatin-glut1-association-abstract].

Functionally, overexpression of stomatin results in a 35-50% reduction in the basal rate of glucose transport, without affecting GLUT1 protein levels or surface expression. This indicates that stomatin decreases the "intrinsic" transport activity of GLUT1 through protein-protein interaction [zhang-2001-stomatin-glut1-abstract].

Notably, stomatin acts as a molecular switch that partly converts GLUT1 from a glucose transporter into a transporter for L-dehydroascorbic acid (DHA), an oxidized form of ascorbic acid. During human erythropoiesis, glucose transport decreases despite a more than 1000-fold increase in GLUT1 transcripts, while GLUT1-mediated DHA transport is dramatically enhanced. Stomatin expression inversely regulates the relative transport of glucose versus DHA by GLUT1. This functional switch appears unique to mammals unable to synthesize vitamin C (humans, apes, guinea pigs), providing a compensatory mechanism for ascorbic acid uptake in species that lack de novo synthesis capability [montel-hagen-2008-dha-uptake-abstract].

4.3 Modulation of Anion Exchanger 1 (AE1/Band 3)

Stomatin also modulates the activity of anion exchanger 1 (AE1, also known as band 3 or SLC4A1), the major erythrocyte membrane protein responsible for Cl⁻/HCO₃⁻ exchange. Proximity ligation assays confirmed direct interaction between stomatin and AE1 in both recombinant cells and erythrocytes [genetet-2017-ae1-modulation-abstract].

Functional studies revealed that stomatin-deficient red blood cells from patients with overhydrated hereditary stomatocytosis exhibit 47% decreased permeability to bicarbonate and 42% decreased chloride efflux compared to normal erythrocytes. Conversely, cells overexpressing stomatin showed 30% elevated AE1 activity compared to cells with only endogenous stomatin expression. Thus, stomatin positively regulates AE1 transport activity through direct protein-protein interaction [genetet-2017-ae1-modulation-abstract].

4.4 Interaction with Aquaporin-1 and Other Transporters

Comprehensive proteomic analysis using chemical cross-linking and mass spectrometry identified additional stomatin interaction partners in erythrocyte membranes. Major partners include GLUT1, AE1 (band 3), and the water channel aquaporin-1 (AQP1). Minor interacting proteins include ferroportin-1, urea transporters, nucleoside transporters, the plasma membrane calcium pump, CD47, and flotillins [rungaldier-2013-stomatin-interactions-abstract].

These findings support a model in which stomatin functions as a membrane-bound scaffolding protein within cholesterol-rich domains, organizing and modulating multiple transport proteins. Immunopurified stomatin complexes analyzed by blue native PAGE revealed major complexes of >500 kDa, approximately 300 kDa, and 130 kDa, all containing stomatin, band 3, and GLUT1 as major components [rungaldier-2013-stomatin-interactions-abstract].

4.5 Modulation of NTCP Bile Salt Transporter in Hepatocytes

Beyond erythrocyte transporters, stomatin regulates bile salt transport in hepatocytes through interaction with the sodium taurocholate cotransporting polypeptide (NTCP/SLC10A1). NTCP is expressed at the basolateral membrane of hepatocytes where it mediates uptake of conjugated bile acids and serves as the hepatocyte entry receptor for hepatitis B and D viruses [appelman-2020-ntcp-bile-abstract].

Proteomic screening identified stomatin as an NTCP-interacting protein, and this interaction was validated in human liver samples, demonstrating physiological relevance. Both stomatin and NTCP localize to lipid rafts at the plasma membrane. Functionally, both stomatin overexpression and knockdown increased NTCP-mediated taurocholate uptake, though the mechanisms differ: in stomatin-depleted cells, NTCP abundance at the plasma membrane increased, while overexpression modulated NTCP function without affecting surface expression [appelman-2020-ntcp-bile-abstract]. This complex regulatory relationship suggests stomatin fine-tunes bile salt uptake through multiple mechanisms, potentially influencing hepatic bile acid homeostasis and viral entry.

5. Role in Cell Division and Lipid Metabolism

5.1 Stomatin in Cytokinesis

Recent research has uncovered an unexpected role for stomatin in cell division. Time-lapse microscopy of stomatin-depleted HeLa cells revealed that the predominant defect is late-stage cytokinesis failure, with a smaller percentage of cells displaying chromosome segregation defects during mitosis [dona-2022-cytokinesis-lipid-abstract]. Proteomic studies have identified stomatin in midbodies, the site of final cleavage between dividing cells, suggesting that stomatin's primary role is during late stages of cytokinesis.

Importantly, key cytokinesis proteins including microtubules, actin, the septin SEPT9, the abscission protein CHMP2A (a member of the ESCRT-III complex), and the cytokinetic regulator RACGAP1 do not mislocalize in stomatin-depleted cells. This indicates that stomatin's effects on cell division are not mediated through gross mislocalization of canonical cytokinesis machinery, but rather through other mechanisms, possibly involving membrane dynamics or lipid organization at the cleavage furrow.

5.2 Stomatin and Lipidome Remodeling

Although stomatin is not a lipid biosynthetic enzyme, its depletion causes significant changes to cellular lipidomes. Specifically, stomatin depletion reduces ether lipids and phosphatidylcholines (PCs) while altering the balance of phosphatidylethanolamine (PE) species [dona-2022-cytokinesis-lipid-abstract]. The overall abundance of PC species decreased, while PE levels showed a net increase.

Remarkably, addition of exogenous phosphatidylcholines rescues stomatin-induced cytokinesis defects, providing direct evidence that stomatin interfaces with lipid metabolism. During cell division, stomatin's mobility on the plasma membrane changes, supporting the requirement for highly regulated physical interactions between membrane lipids and this cell division protein [dona-2022-cytokinesis-lipid-abstract]. These findings connect stomatin's established role as a lipid raft-associated scaffolding protein with new functions in regulating membrane lipid composition during critical cellular processes.

6. Evolutionary Conservation: Lessons from the C. elegans Homolog MEC-2

6.1 MEC-2 in Touch Sensation

The significance of stomatin in mechanosensation was first established through studies of its nematode homolog MEC-2 in Caenorhabditis elegans. The mec-2 gene is required for the function of six touch receptor neurons; mutants are touch-insensitive despite morphologically normal touch cells. The central region of MEC-2 shows high similarity to human stomatin, suggesting conserved function [huang-1995-mec2-abstract].

MEC-2-LacZ fusion proteins localize along the processes of touch receptor neurons, with this localization requiring an N-terminal signal disrupted by mutations in mec-12 (α-tubulin). This led to the hypothesis that MEC-2 links the mechanosensory channel to the microtubule cytoskeleton, enabling mechanotransduction through microtubule displacement-triggered channel activation [huang-1995-mec2-abstract].

6.2 MEC-2 Regulation of DEG/ENaC Channels

Electrophysiological studies demonstrated that MEC-2 dramatically enhances the activity of the mechanosensory channel complex formed by MEC-4 and MEC-10 (members of the DEG/ENaC family). When co-expressed in Xenopus oocytes, MEC-2 increased channel activity approximately 40-fold and allowed currents to be detected with wild-type MEC-4/MEC-10 that were undetectable without MEC-2 [goodman-2002-mec2-degenac-abstract].

Interestingly, while stomatin typically inhibits channel currents (as with ASIC3), MEC-2 potentiates MEC-4/MEC-10 activity. This suggests that stomatin-domain proteins can either enhance or suppress ion channel activity depending on the specific channel and cellular context. The conserved presence of stomatin-like proteins and DEG/ENaC family channels across vertebrates and invertebrates implies that this regulatory relationship has ancient evolutionary origins and may have important implications for mammalian mechanosensation and nociception [goodman-2002-mec2-degenac-abstract, price-2004-stomatin-asic-abstract].

6.3 Phase Transitions in Mechanotransduction

Recent work has revealed that MEC-2 undergoes liquid-to-solid phase transitions that are functionally important. In a liquid-like state, MEC-2 condensates facilitate transport along neurites with varying caliber. Upon reaching their cellular target, MEC-2 condensates transition to a solid-like state capable of sustaining mechanical stress over long timescales during body wall touch, providing a focus for force transmission to the ion channel.

7. The Stomatin Family: STOML1, STOML2, STOML3, and Podocin

7.1 Overview of Family Members

The human genome encodes five stomatin-related genes: STOM (stomatin), STOML1, STOML2, STOML3, and NPHS2 (podocin). All share a conserved stomatin/SPFH domain and the capacity for membrane association, though they differ in expression patterns and specific functions.

STOML1 is highly expressed in brain and at lower levels in heart, skeletal muscle, and dorsal root ganglion sensory neurons where, like stomatin, it modulates ASIC channel activity. STOML2 localizes to mitochondria where it binds cardiolipin, stabilizing the inner mitochondrial membrane and creating scaffolds for supramolecular respiratory complexes. STOML2 lacks the typical N-terminal hydrophobic membrane anchor of other family members.

7.2 STOML3 in Piezo Channel Sensitization

STOML3 has emerged as particularly important for mechanosensation in sensory neurons. In mouse skin mechanoreceptors, molecular-scale displacements of approximately 13 nm are sufficient to gate mechanosensitive currents. Remarkably, in the absence of STOML3, displacement thresholds increase by one order of magnitude. STOML3 brings the activation threshold for Piezo1 and Piezo2 channels down to approximately 10 nm, enabling detection of molecular-scale stimuli relevant for fine touch [poole-2014-piezo-tuning-abstract].

STOML3 achieves this sensitization by controlling membrane mechanics through cholesterol binding. STOML3 localizes to cholesterol-rich lipid rafts, and in sensory neurons, cholesterol depletion and STOML3 deficiency similarly attenuate mechanosensitivity while modulating membrane mechanics [qi-2015-stoml3-membrane-stiffening-abstract]. This mechanism has therapeutic implications: small-molecule inhibitors of STOML3 oligomerization have been developed that effectively silence touch receptors and reverse touch-evoked pain associated with nerve injury or diabetic neuropathy, suggesting the STOML3-cholesterol interaction as a potential target for chronic pain management.

7.3 Podocin in Kidney Function

Podocin (NPHS2) is specifically localized to the slit diaphragm of podocytes, specialized epithelial cells covering kidney glomerular capillaries. Sharing approximately 44% homology with stomatin through its conserved PHB domain, podocin interacts with nephrin, NEPH1, and the TRPC6 calcium channel. Podocin acts as a molecular switch determining the preferred mode of TRPC6 activation: it reduces sensitivity to mechanical stimuli while facilitating activation by diacylglycerol analogs.

Mutations in NPHS2 cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS), accounting for approximately 18% of SRNS cases. More than 100 different NPHS2 mutations have been identified. Loss of podocin function would result in profound hyperactivation of TRPC6 channels in foot processes, potentially leading to calcium overload as a shared pathogenic mechanism in glomerular diseases caused by mutations in either NPHS2 or TRPC6 genes.

8. Role in Innate Immunity

8.1 Stomatin in Macrophage Antifungal Defense

Recent studies have revealed an important role for stomatin in innate immune function, particularly in macrophage responses to fungal pathogens. Using CRISPR/Cas9-generated stomatin-deficient macrophage cell lines, researchers demonstrated that stomatin is required for optimal phagocytosis of Aspergillus fumigatus conidia, a major human fungal pathogen [goldmann-2023-dectin1-macrophage-abstract].

Mechanistically, stomatin is involved in the recruitment of the β-glucan receptor dectin-1 to both the plasma membrane and the phagosomal membrane. In stomatin knockout macrophages, only 30% of cells were dectin-1 positive after 24 hours of culture, compared to 70% of wild-type cells. Furthermore, stomatin promotes phagosome maturation by fostering fusion of phagosomes with lysosomes. In stomatin-deficient cells infected with pigmentless conidia, phagosome-lysosome fusion was reduced, vATPase recruitment to phagosomes was impaired, and tumor necrosis factor alpha (TNF-α) production was diminished [goldmann-2023-dectin1-macrophage-abstract]. These findings establish stomatin as a lipid raft component that facilitates pathogen recognition receptor localization and phagosomal maturation during antifungal immunity.

8.2 Stomatin in Neutrophil Function

Stomatin also plays a role in neutrophil biology, with particular relevance to inflammatory conditions. Stomatin expression is upregulated in neutrophils following severe burn injury, where it promotes neutrophil degranulation and contributes to vascular leakage and lung damage during the early inflammatory response. Mechanistically, stomatin enhances the binding of primary granules to the cytoskeletal protein F-actin, facilitating granule mobilization and content release.

Importantly, genetic knockout of stomatin in mice partially inhibited excessive neutrophil degranulation following burn injury, potentially by reducing primary granule production and weakening granule-cytoskeleton interactions. Stomatin-deficient mice showed significantly reduced lung injury and vascular leakage compared to wild-type animals. These findings suggest that stomatin may represent a therapeutic target for controlling excessive inflammation in conditions characterized by neutrophil hyperactivation.

9. Disease Associations

9.1 Overhydrated Hereditary Stomatocytosis (OHSt)

Stomatin is notably absent from erythrocyte membranes in overhydrated hereditary stomatocytosis (OHSt), a variably compensated macrocytic hemolytic anemia characterized by red cells with slit-like lucencies (stomata), markedly increased cation permeability, and erythrocyte overhydration. Paradoxically, no mutations in the STOM gene have been identified in OHSt patients; stomatin protein production appears normal, suggesting that loss of stomatin is a secondary change [fricke-2005-ohst-trafficking-abstract].

Studies of erythroid cell cultures from OHSt patients revealed that stomatin immunoreactivity is present in progenitor cells but remains restricted to multivesicular complexes and the nuclear area during development, never reaching the plasma membrane. This suggests stomatin is "an innocent passenger in a more fundamental trafficking abnormality" [fricke-2005-ohst-trafficking-abstract].

OHSt is actually caused by heterozygous mutations in the RHAG gene (encoding Rh-associated glycoprotein), with the F65S mutation representing a hotspot. The RHAG mutations occur in predicted transmembrane regions and are thought to widen the pore, allowing cation passage. The mechanism by which RHAG mutations lead to stomatin mistrafficking remains incompletely understood.

Functionally, stomatin-deficient erythrocytes from OHSt patients exhibit approximately 50% reduction in Cl⁻/HCO₃⁻ exchange activity, while glucose uptake is increased and DHA transport is decreased. The absence of stomatin thus has measurable consequences for erythrocyte transport function [genetet-2017-ae1-modulation-abstract, montel-hagen-2008-dha-uptake-abstract].

9.2 Cancer Associations

Altered stomatin expression has been reported in various cancers. Decreased stomatin expression predicts poor prognosis in HER2-positive breast cancer. Stomatin's ability to control neutrophil degranulation, modulate transporter protein activity, and influence membrane organization may contribute to its roles in cancer progression and metastasis. The mechanisms underlying these associations remain areas of active investigation.

10. Open Questions

Several important questions about stomatin biology remain unresolved:

1. Mechanism of OHSt pathogenesis: Why do RHAG mutations lead to stomatin mistrafficking? What is the functional relationship between RhAG and stomatin that causes secondary stomatin loss?

2. Selectivity of ion channel modulation: Why does stomatin inhibit some channels (ASIC3) while its homolog MEC-2 potentiates others (MEC-4/MEC-10)? What determines whether a stomatin-domain protein will enhance or suppress channel activity?

3. Dynamics of oligomer assembly: How is stomatin oligomerization regulated in cells? What signals control the assembly and disassembly of stomatin ring structures, and how does this relate to functional states?

4. Coordination with other scaffolding proteins: How do stomatin, flotillins, and prohibitins cooperate or compete in organizing membrane domains? Do they form higher-order hetero-oligomeric complexes?

5. Cell division mechanisms: How does stomatin influence lipid metabolism and membrane dynamics during cytokinesis? Does stomatin interact directly with cytokinesis machinery or act indirectly through lipid organization?

6. Immune function specificity: What determines stomatin's differential effects on macrophage versus neutrophil function? Are these tissue-specific adaptations of a common scaffolding mechanism?

7. Therapeutic potential: Can stomatin-targeting compounds be developed for chronic pain management, inflammatory disorders, or cancer? The success of STOML3 oligomerization blockers in pain models provides proof-of-concept but stomatin-specific therapeutics remain unexplored.

8. NTCP regulation and viral entry: Does stomatin's modulation of NTCP affect hepatitis B/D virus entry into hepatocytes? Could targeting this interaction have antiviral therapeutic applications?

11. References

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Citations

1. appelman-2020-ntcp-bile-abstract.md
2. brand-2012-stomatin-dimer-abstract.md
3. dona-2022-cytokinesis-lipid-abstract.md
4. fricke-2005-ohst-trafficking-abstract.md
5. genetet-2017-ae1-modulation-abstract.md
6. goldmann-2023-dectin1-macrophage-abstract.md
7. goodman-2002-mec2-degenac-abstract.md
8. hiebl-dirschmied-1991-cloning-abstract.md
9. huang-1995-mec2-abstract.md
10. kadurin-2009-proline-topology-abstract.md
11. mairhofer-2002-platelet-abstract.md
12. montel-hagen-2008-dha-uptake-abstract.md
13. poole-2014-piezo-tuning-abstract.md
14. price-2004-stomatin-asic-abstract.md
15. qi-2015-stoml3-membrane-stiffening-abstract.md
16. rungaldier-2013-stomatin-interactions-abstract.md
17. rungaldier-2017-stomatin-structure-function-abstract.md
18. zhang-1999-stomatin-glut1-association-abstract.md
19. zhang-2001-stomatin-glut1-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan and verification
- Target identity: STOM encodes human stomatin (UniProt P27105), historically identified as erythrocyte “band 7/band 7.2” integral membrane protein. It belongs to the SPFH (stomatin–prohibitin–flotillin–HflK/C) superfamily and contains the Band-7/stomatin-like domain, consistent with the UniProt domains provided. Human organism context applies throughout. Supporting literature below uses human erythrocytes or cross-species SPFH principles with explicit human relevance (e.g., RBC studies, human GLUT1 links) (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, murphy2004erythrocytedetergentresistantmembrane pages 1-2, lu2024molecularmechanismof pages 1-3).

Comprehensive research report on human STOM (stomatin; UniProt P27105)

1) Key concepts and definitions
- Molecular identity and family: Stomatin is an integral membrane-associated scaffolding protein of the SPFH superfamily (stomatin, prohibitin, flotillin, HflK/C) that organizes cholesterol-rich, detergent-resistant plasma-membrane microdomains (“rafts”) and regulates associated transporters and channels. In erythrocytes it corresponds to band 7/band 7.2 protein (historical nomenclature) (https://doi.org/10.1182/blood-2010-12-326645; https://doi.org/10.1182/blood-2003-09-3165; https://doi.org/10.1101/2024.05.25.595881) (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, murphy2004erythrocytedetergentresistantmembrane pages 1-2, lu2024molecularmechanismof pages 1-3).
- Canonical functions: (i) membrane microdomain scaffolding; (ii) modulation of transporters and ion channels (notably GLUT1 in erythrocytes; ASIC/ENaC/DEG family and pannexin-1 in neurons/other cells are modulated by stomatin-domain proteins); (iii) potential roles in mechanosensation via SPFH family mechanisms (https://doi.org/10.1182/blood-2010-12-326645; https://doi.org/10.1152/ajprenal.00546.2019) (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, carattino2020acidsensingionchannels pages 1-6).
- Subcellular localization: Stomatin is enriched in detergent-resistant membrane (DRM) fractions of human erythrocyte membranes (rafts) and is part of the plasma membrane macrocomplex landscape (https://doi.org/10.1182/blood-2003-09-3165) (murphy2004erythrocytedetergentresistantmembrane pages 1-2).

2) Current understanding of molecular mechanisms and complexes
- Membrane microdomains and SPFH architecture: SPFH proteins share a conserved SPFH domain followed by a long coiled-coil that mediates oligomerization and membrane association (often via palmitoylation/myristoylation and cholesterol interaction motifs). Recent structural work on human flotillin (another SPFH member) shows alternating FLOT1/FLOT2 hetero-oligomers assembling into a dome-shaped 44-mer that encage ~30 nm patches of the cytoplasmic leaflet, offering a mechanistic paradigm for SPFH scaffolds that likely generalizes to stomatin’s microdomain organization (https://doi.org/10.1101/2024.05.25.595881; bioRxiv, 2024) (lu2024molecularmechanismof pages 1-3).
- Stomatin oligomerization and domain organization (emerging): Cryo-EM of human stomatin suggests 16-mer bowl-shaped oligomers that cluster on membranes and increase lipid order, consistent with a direct role in organizing functional microdomains (bioRxiv 2025; https://doi.org/10.1101/2025.08.30.673307). Super-resolution imaging reports stomatin clusters ~50–150 nm in diameter in cells; polymerization-deficient mutants fail to enhance lipid order, supporting a polymerization-dependent scaffolding mechanism (yan2025structuralroleof pages 1-5, yan2025structuralroleof pages 28-33, yan2025structuralroleof pages 5-9, yan2025structuralroleof pages 9-13, yan2025structuralroleof pages 33-40, yan2025structuralroleof pages 22-26). Although 2025 and preprint, these data are congruent with SPFH microdomain models anchored by 2024 flotillin cryo-EM (lu2024molecularmechanismof pages 1-3).
- RBC raft biology and selective cargo: In human erythrocytes, stomatin is a major DRM component alongside band 3 (SLC4A1) and flotillins. During P. falciparum infection, some DRM proteins (flotillins) are recruited to the parasitophorous vacuole, while others (band 3, stomatin) are excluded, indicating selective raft protein uptake and highlighting stomatin’s membrane microdomain context (https://doi.org/10.1182/blood-2003-09-3165) (murphy2004erythrocytedetergentresistantmembrane pages 1-2).

3) Transporters/channels regulated by stomatin and pathway placement
- GLUT1 (SLC2A1) in erythrocytes: Stomatin associates with erythrocyte GLUT1; this association has been reported to switch GLUT1′s preference toward L-dehydroascorbic acid (DHA) transport during terminal erythroid maturation, a primate strategy to import vitamin C equivalents. In stomatin-deficient cryohydrocytosis (sdCHC), pathogenic SLC2A1 variants produce RBCs that lack stomatin and exhibit both impaired glucose transport and a cation leak when mutant GLUT1 is expressed in oocytes, defining a GLUT1-linked hereditary stomatocytosis variant (Blood, 2011; https://doi.org/10.1182/blood-2010-12-326645). These data establish a functional STOM–GLUT1 axis with physiological consequences in RBCs (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, flatt2011stomatindeficientcryohydrocytosisresults pages 12-12).
- ASICs/ENaC/DEG family: In mammals, stomatin-domain proteins are part of the protein networks that modulate acid-sensing ion channels (ASICs), which are involved in mechanotransduction, nociception, and chemoreception. Reviews emphasize their association within membrane microdomains and tethering networks, placing stomatin proteins as modulators of ASIC gating/trafficking in sensory neurons (Am J Physiol-Renal Physiol 2020; https://doi.org/10.1152/ajprenal.00546.2019) (carattino2020acidsensingionchannels pages 1-6).

4) Subcellular localization and tissue distribution
- Erythrocytes: Stomatin is abundant in human erythrocyte membranes, enriched in DRM (raft) fractions, and often studied as part of the RBC membrane macrocomplex milieu (https://doi.org/10.1182/blood-2003-09-3165) (murphy2004erythrocytedetergentresistantmembrane pages 1-2).
- Developmental dynamics: During reticulocyte maturation, stomatin is reduced through endocytic/exosomal pathways; its levels define erythroid maturation states in some studies (Blood 2011; contextual citations within) (flatt2011stomatindeficientcryohydrocytosisresults pages 12-12).
- Other tissues/cells: While detailed human tissue distribution was not directly quantified in the retrieved 2023–2024 sources, SPFH roles are broadly conserved across cell types; flotillin structural data (2024) and stomatin oligomerization (2025 preprint) indicate generalizable membrane-scaffold functions beyond erythrocytes (https://doi.org/10.1101/2024.05.25.595881; https://doi.org/10.1101/2025.08.30.673307) (lu2024molecularmechanismof pages 1-3, yan2025structuralroleof pages 1-5).

5) Disease associations and clinical relevance
- Stomatin-deficient cryohydrocytosis (sdCHC; hereditary stomatocytosis variant): Patients harbor SLC2A1 mutations; RBCs lack stomatin and display cold-induced cation leak, hemolytic anemia, hepatosplenomegaly, and neurological manifestations typical of GLUT1 deficiency. Heterologous expression of mutant GLUT1 recapitulates cation leak and transport defects. sdCHC establishes a clinico-genetic link between GLUT1 and stomatin deficiency at the RBC membrane (Blood, 2011; https://doi.org/10.1182/blood-2010-12-326645) (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, flatt2011stomatindeficientcryohydrocytosisresults pages 12-12).
- Broader hydration disorders: Reviews of erythrocyte hydration disorders highlight GLUT1, SLC4A1, RHAG, PIEZO1, KCNN4 as key contributors and contextualize stomatin within the RBC membrane network; OHSt/RHAG variants produce monovalent cation leaks, with stomatin loss noted in some phenotypes, reinforcing its diagnostic/molecular milieu (Blood, 2017; https://doi.org/10.1182/blood-2017-04-590810) (gallagher2017disordersoferythrocyte pages 1-5).

6) Recent developments (emphasis 2023–2024) and expert perspectives
- RBC GLUT1 knockout study (2024): CRISPR-engineered human erythroblasts and primary CD34+ progenitors generated reticulocytes lacking GLUT1. Despite GLUT1’s abundance (~200,000 copies/cell; ~10% of RBC membrane protein mass), complete absence did not impede erythroblast proliferation, differentiation, enucleation, or reticulocyte membrane composition/deformability, though metabolic adaptations, increased osmotic fragility, and oxidative stress hallmarks were noted. This study recapitulates that reduced GLUT1 expression alone does not cause anemia in GLUT1 deficiency, and it explicitly situates GLUT1 within a membrane complex with stomatin/adducin/dematin in human RBCs (bioRxiv, 2024; https://doi.org/10.1101/2024.01.10.574621). These data refine expectations of the stomatin–GLUT1 axis by separating erythropoiesis and mechanics from metabolism and antioxidant capacity in the absence of GLUT1 (freire2024completeabsenceof pages 1-3, freire2024completeabsenceof pages 3-5).
- SPFH structural paradigm (2024): Cryo-EM of human flotillin complexes (3.57 Å) demonstrates large dome/ring oligomers that segregate ~30 nm membrane microdomains, supporting a general SPFH-based mechanism for microdomain formation and protein sequestration relevant to stomatin (bioRxiv, 2024; https://doi.org/10.1101/2024.05.25.595881) (lu2024molecularmechanismof pages 1-3).
- Emerging stomatin structural insights (2025 preprint): Cryo-EM and cell imaging suggest human stomatin forms 16-mer bowls, organizes 50–150 nm microdomains, and increases lipid order, offering a plausible structural basis for stomatin’s raft scaffolding and cargo regulation (https://doi.org/10.1101/2025.08.30.673307). While outside the 2023–2024 window and preprint, the findings align with the 2024 flotillin structures and with historical RBC raft evidence (yan2025structuralroleof pages 1-5, yan2025structuralroleof pages 28-33, yan2025structuralroleof pages 5-9, yan2025structuralroleof pages 9-13, yan2025structuralroleof pages 33-40).
- ASICs and stomatin-domain proteins (2020 review, with 2023–2024 ASIC literature context): Reviews underscore stomatin-domain proteins as part of ASIC regulatory networks in sensory neurons and other tissues, integrating mechanotransduction and chemosensation in lipid-raft contexts (Am J Physiol-Renal Physiol, 2020; https://doi.org/10.1152/ajprenal.00546.2019) (carattino2020acidsensingionchannels pages 1-6).

7) Current applications and real-world implementations
- Hematology diagnostics and mechanistic models: Stomatin serves as a biochemical marker in RBC DRM fractions and is informative in classifying hereditary stomatocytosis subtypes with membrane-protein macrocomplex defects (Blood, 2011; Blood, 2017). Selective recruitment/exclusion of raft proteins (e.g., stomatin excluded) during malaria infection of RBCs provides an experimental model to probe host–pathogen interactions and raft function (Blood, 2004; https://doi.org/10.1182/blood-2003-09-3165) (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, gallagher2017disordersoferythrocyte pages 1-5, murphy2004erythrocytedetergentresistantmembrane pages 1-2).
- Membrane microdomain scaffolds as targets: Structural definition of SPFH complexes (flotillin, 2024) supports rational exploration of microdomain-modulating strategies (e.g., cholesterol/raft perturbation) in trafficking and signaling, with translational implications across cell types (https://doi.org/10.1101/2024.05.25.595881) (lu2024molecularmechanismof pages 1-3).

8) Relevant statistics and quantitative data
- Abundance of GLUT1 in human RBCs: ~200,000 copies per cell, accounting for ~10% of total RBC membrane protein mass; stomatin is part of the same RBC membrane macro-environment (bioRxiv, 2024; https://doi.org/10.1101/2024.01.10.574621) (freire2024completeabsenceof pages 1-3).
- DRM composition in RBCs: Band 3 and stomatin reflect bulk DRM mass; flotillin-1/-2 and peroxiredoxin-2 are additional DRM constituents (Blood, 2004; https://doi.org/10.1182/blood-2003-09-3165) (murphy2004erythrocytedetergentresistantmembrane pages 1-2).
- SPFH microdomain dimensions: Flotillin complex encloses ~30 nm circular membrane patches (bioRxiv, 2024; https://doi.org/10.1101/2024.05.25.595881). Stomatin clusters reported at ~50–150 nm (preprint, 2025; https://doi.org/10.1101/2025.08.30.673307) (lu2024molecularmechanismof pages 1-3, yan2025structuralroleof pages 33-40).

9) Expert analysis and synthesis
- Primary role: Stomatin is best defined as a membrane microdomain scaffold/regulator rather than an enzyme or classical transporter. Its most strongly supported, specific interaction in human biology is with GLUT1 in erythrocytes, where it contributes to substrate preference switching toward DHA during maturation and participates in macrocomplex organization affecting ion homeostasis. The sdCHC entity links stomatin absence and GLUT1 dysfunction with cation leaks and hemolysis, underscoring functional coupling between raft scaffolds and solute transport (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, flatt2011stomatindeficientcryohydrocytosisresults pages 12-12).
- Broader signaling roles: Through SPFH-mediated oligomerization and raft organization, stomatin can influence the biophysical environment of ion channels and transporters (ASICs, pannexin-1, AE1 macrocomplex neighbors), providing a mechanistic basis for pleiotropic influences on mechanosensation and chemosensation described for stomatin-domain proteins (carattino2020acidsensingionchannels pages 1-6, murphy2004erythrocytedetergentresistantmembrane pages 1-2).
- 2023–2024 priorities: The 2024 human RBC GLUT1 knockout work refines the clinical interpretation of GLUT1 deficiency vis-à-vis RBCs and highlights that absence of GLUT1 (and thus loss of any stomatin–GLUT1 interaction) can be tolerated in erythroid differentiation, while altering metabolic resilience. Parallel SPFH structural advances (flotillin) provide a generalizable template for stomatin’s microdomain architecture, now complemented by emerging stomatin cryo-EM in 2025 preprints (freire2024completeabsenceof pages 1-3, lu2024molecularmechanismof pages 1-3, yan2025structuralroleof pages 1-5).

10) Gaps and future directions (brief)
- High-resolution human stomatin structures in peer-reviewed journals and in the 2023–2024 window remain a gap; preprint data are promising but require validation. Quantitative, in vivo human evidence for stomatin’s modulation of specific channels (e.g., ASICs) and transporters beyond GLUT1 in defined tissues remains to be elaborated.

References (URLs and years)
- Flatt et al., Blood, 2011. “Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1.” https://doi.org/10.1182/blood-2010-12-326645 (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, flatt2011stomatindeficientcryohydrocytosisresults pages 12-12).
- Murphy et al., Blood, 2004. “Erythrocyte detergent-resistant membrane proteins…” https://doi.org/10.1182/blood-2003-09-3165 (murphy2004erythrocytedetergentresistantmembrane pages 1-2).
- Carattino & Montalbetti, Am J Physiol-Renal Physiol, 2020. “Acid-sensing ion channels in sensory signaling.” https://doi.org/10.1152/ajprenal.00546.2019 (carattino2020acidsensingionchannels pages 1-6).
- Gallagher, Blood, 2017. “Disorders of erythrocyte hydration.” https://doi.org/10.1182/blood-2017-04-590810 (gallagher2017disordersoferythrocyte pages 1-5).
- Freire et al., bioRxiv, 2024. “Complete absence of GLUT1 does not impair human terminal erythroid differentiation.” https://doi.org/10.1101/2024.01.10.574621 (freire2024completeabsenceof pages 1-3, freire2024completeabsenceof pages 3-5).
- Lu et al., bioRxiv, 2024. “Molecular mechanism of the flotillin complex in membrane microdomain organization.” https://doi.org/10.1101/2024.05.25.595881 (lu2024molecularmechanismof pages 1-3).
- Yan et al., bioRxiv, 2025. “Structural role of stomatin in organizing functional membrane microdomains.” https://doi.org/10.1101/2025.08.30.673307 (yan2025structuralroleof pages 1-5, yan2025structuralroleof pages 28-33, yan2025structuralroleof pages 5-9, yan2025structuralroleof pages 9-13, yan2025structuralroleof pages 33-40, yan2025structuralroleof pages 22-26).

Conclusion
Human stomatin (STOM) is a membrane microdomain scaffold of the SPFH family, abundant in erythrocyte rafts and mechanistically positioned to regulate transporter and ion channel function through oligomeric organization of lipid-ordered domains. The stomatin–GLUT1 interaction in RBCs is the clearest, historically supported example, relevant to substrate preference (DHA transport) and to pathophysiology in sdCHC. Recent 2024 studies advance our understanding of RBC membrane biology (GLUT1 deletion tolerance) and SPFH architecture (flotillin cryo-EM), while 2025 preprints supply direct structural hypotheses for human stomatin assemblies that align with the broader SPFH paradigm (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3, murphy2004erythrocytedetergentresistantmembrane pages 1-2, freire2024completeabsenceof pages 1-3, lu2024molecularmechanismof pages 1-3, yan2025structuralroleof pages 1-5).

References

1. (flatt2011stomatindeficientcryohydrocytosisresults pages 1-3): Joanna F. Flatt, Hélène Guizouarn, Nicholas M. Burton, Franck Borgese, Richard J. Tomlinson, Robert J. Forsyth, Stephen A. Baldwin, Bari E. Levinson, Philippe Quittet, Patricia Aguilar-Martinez, Jean Delaunay, Gordon W. Stewart, and Lesley J. Bruce. Stomatin-deficient cryohydrocytosis results from mutations in slc2a1: a novel form of glut1 deficiency syndrome. Blood, 118 19:5267-77, Nov 2011. URL: https://doi.org/10.1182/blood-2010-12-326645, doi:10.1182/blood-2010-12-326645. This article has 103 citations and is from a highest quality peer-reviewed journal.

2. (murphy2004erythrocytedetergentresistantmembrane pages 1-2): Sean C. Murphy, Benjamin U. Samuel, Travis Harrison, Kaye D. Speicher, David W. Speicher, Marion E. Reid, Rainer Prohaska, Philip S. Low, Michael J. Tanner, Narla Mohandas, and Kasturi Haldar. Erythrocyte detergent-resistant membrane proteins: their characterization and selective uptake during malarial infection. Blood, 103 5:1920-8, Mar 2004. URL: https://doi.org/10.1182/blood-2003-09-3165, doi:10.1182/blood-2003-09-3165. This article has 192 citations and is from a highest quality peer-reviewed journal.

3. (lu2024molecularmechanismof pages 1-3): Ming-Ao Lu, Yunwen Qian, Liangwen Ma, Qiang Guo, and Ning Gao. Molecular mechanism of the flotillin complex in membrane microdomain organization. bioRxiv, May 2024. URL: https://doi.org/10.1101/2024.05.25.595881, doi:10.1101/2024.05.25.595881. This article has 7 citations and is from a poor quality or predatory journal.

4. (carattino2020acidsensingionchannels pages 1-6): Marcelo D. Carattino and Nicolas Montalbetti. Acid-sensing ion channels in sensory signaling. American Journal of Physiology-Renal Physiology, 318:F531-F543, Mar 2020. URL: https://doi.org/10.1152/ajprenal.00546.2019, doi:10.1152/ajprenal.00546.2019. This article has 46 citations and is from a peer-reviewed journal.

5. (yan2025structuralroleof pages 1-5): Lu Yan, Xinyue Zhou, Meiqi Li, Chenxi Wang, Bailong Xiao, Peng Xi, Peng Zou, and Ning Gao. Structural role of stomatin in organizing functional membrane microdomains. BioRxiv, Sep 2025. URL: https://doi.org/10.1101/2025.08.30.673307, doi:10.1101/2025.08.30.673307. This article has 0 citations and is from a poor quality or predatory journal.

6. (yan2025structuralroleof pages 28-33): Lu Yan, Xinyue Zhou, Meiqi Li, Chenxi Wang, Bailong Xiao, Peng Xi, Peng Zou, and Ning Gao. Structural role of stomatin in organizing functional membrane microdomains. BioRxiv, Sep 2025. URL: https://doi.org/10.1101/2025.08.30.673307, doi:10.1101/2025.08.30.673307. This article has 0 citations and is from a poor quality or predatory journal.

7. (yan2025structuralroleof pages 5-9): Lu Yan, Xinyue Zhou, Meiqi Li, Chenxi Wang, Bailong Xiao, Peng Xi, Peng Zou, and Ning Gao. Structural role of stomatin in organizing functional membrane microdomains. BioRxiv, Sep 2025. URL: https://doi.org/10.1101/2025.08.30.673307, doi:10.1101/2025.08.30.673307. This article has 0 citations and is from a poor quality or predatory journal.

8. (yan2025structuralroleof pages 9-13): Lu Yan, Xinyue Zhou, Meiqi Li, Chenxi Wang, Bailong Xiao, Peng Xi, Peng Zou, and Ning Gao. Structural role of stomatin in organizing functional membrane microdomains. BioRxiv, Sep 2025. URL: https://doi.org/10.1101/2025.08.30.673307, doi:10.1101/2025.08.30.673307. This article has 0 citations and is from a poor quality or predatory journal.

9. (yan2025structuralroleof pages 33-40): Lu Yan, Xinyue Zhou, Meiqi Li, Chenxi Wang, Bailong Xiao, Peng Xi, Peng Zou, and Ning Gao. Structural role of stomatin in organizing functional membrane microdomains. BioRxiv, Sep 2025. URL: https://doi.org/10.1101/2025.08.30.673307, doi:10.1101/2025.08.30.673307. This article has 0 citations and is from a poor quality or predatory journal.

10. (yan2025structuralroleof pages 22-26): Lu Yan, Xinyue Zhou, Meiqi Li, Chenxi Wang, Bailong Xiao, Peng Xi, Peng Zou, and Ning Gao. Structural role of stomatin in organizing functional membrane microdomains. BioRxiv, Sep 2025. URL: https://doi.org/10.1101/2025.08.30.673307, doi:10.1101/2025.08.30.673307. This article has 0 citations and is from a poor quality or predatory journal.

11. (flatt2011stomatindeficientcryohydrocytosisresults pages 12-12): Joanna F. Flatt, Hélène Guizouarn, Nicholas M. Burton, Franck Borgese, Richard J. Tomlinson, Robert J. Forsyth, Stephen A. Baldwin, Bari E. Levinson, Philippe Quittet, Patricia Aguilar-Martinez, Jean Delaunay, Gordon W. Stewart, and Lesley J. Bruce. Stomatin-deficient cryohydrocytosis results from mutations in slc2a1: a novel form of glut1 deficiency syndrome. Blood, 118 19:5267-77, Nov 2011. URL: https://doi.org/10.1182/blood-2010-12-326645, doi:10.1182/blood-2010-12-326645. This article has 103 citations and is from a highest quality peer-reviewed journal.

12. (gallagher2017disordersoferythrocyte pages 1-5): Patrick G. Gallagher. Disorders of erythrocyte hydration. Blood, 130 25:2699-2708, Dec 2017. URL: https://doi.org/10.1182/blood-2017-04-590810, doi:10.1182/blood-2017-04-590810. This article has 141 citations and is from a highest quality peer-reviewed journal.

13. (freire2024completeabsenceof pages 1-3): CM Freire, NR King, M Dzieciatkowska, D Stephenson, PL Moura, J.G.G Dobbe, GJ Streekstra, A D’Alessandro, AM Toye, and TJ Satchwell. Complete absence of glut1 does not impair human terminal erythroid differentiation. bioRxiv, Jan 2024. URL: https://doi.org/10.1101/2024.01.10.574621, doi:10.1101/2024.01.10.574621. This article has 6 citations and is from a poor quality or predatory journal.

14. (freire2024completeabsenceof pages 3-5): CM Freire, NR King, M Dzieciatkowska, D Stephenson, PL Moura, J.G.G Dobbe, GJ Streekstra, A D’Alessandro, AM Toye, and TJ Satchwell. Complete absence of glut1 does not impair human terminal erythroid differentiation. bioRxiv, Jan 2024. URL: https://doi.org/10.1101/2024.01.10.574621, doi:10.1101/2024.01.10.574621. This article has 6 citations and is from a poor quality or predatory journal.

Citations

1. murphy2004erythrocytedetergentresistantmembrane pages 1-2
2. lu2024molecularmechanismof pages 1-3
3. carattino2020acidsensingionchannels pages 1-6
4. flatt2011stomatindeficientcryohydrocytosisresults pages 12-12
5. gallagher2017disordersoferythrocyte pages 1-5
6. freire2024completeabsenceof pages 1-3
7. flatt2011stomatindeficientcryohydrocytosisresults pages 1-3
8. yan2025structuralroleof pages 1-5
9. yan2025structuralroleof pages 28-33
10. yan2025structuralroleof pages 5-9
11. yan2025structuralroleof pages 9-13
12. yan2025structuralroleof pages 33-40
13. yan2025structuralroleof pages 22-26
14. freire2024completeabsenceof pages 3-5
15. https://doi.org/10.1182/blood-2010-12-326645;
16. https://doi.org/10.1182/blood-2003-09-3165;
17. https://doi.org/10.1101/2024.05.25.595881
18. https://doi.org/10.1152/ajprenal.00546.2019
19. https://doi.org/10.1182/blood-2003-09-3165
20. https://doi.org/10.1101/2024.05.25.595881;
21. https://doi.org/10.1101/2025.08.30.673307
22. https://doi.org/10.1182/blood-2010-12-326645
23. https://doi.org/10.1182/blood-2017-04-590810
24. https://doi.org/10.1101/2024.01.10.574621
25. https://doi.org/10.1182/blood-2010-12-326645,
26. https://doi.org/10.1182/blood-2003-09-3165,
27. https://doi.org/10.1101/2024.05.25.595881,
28. https://doi.org/10.1152/ajprenal.00546.2019,
29. https://doi.org/10.1101/2025.08.30.673307,
30. https://doi.org/10.1182/blood-2017-04-590810,
31. https://doi.org/10.1101/2024.01.10.574621,

STOM Gene (Human Stomatin) – Structure, Function, and Localization

Overview of Stomatin (STOM)

Stomatin is a widely expressed membrane protein encoded by the human STOM gene (UniProt P27105). It belongs to the stomatin/prohibitin/flotillin/HflK/C (SPFH) superfamily (also called the band-7 family) of membrane proteins, which are known for organizing lipid microdomains (pubmed.ncbi.nlm.nih.gov). Stomatin is a ~31 kDa integral membrane protein that attaches to the cytosolic side of the plasma membrane via a hydrophobic segment (residues 26–54) in a hairpin-like insertion (pmc.ncbi.nlm.nih.gov). Both its N- and C-termini face the cytoplasm, consistent with a monotopic membrane topology (pmc.ncbi.nlm.nih.gov). Stomatin was first identified in human red blood cell (RBC) membranes (historically termed band 7.2b), and it was named for its absence in overhydrated hereditary stomatocytosis (OHSt), a condition where stomatin-deficient RBCs exhibit abnormal “stomatocyte” morphology (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The protein is highly conserved across species, with homologs like MEC-2 in C. elegans and podocin in kidney cells, reflecting its fundamental role in membrane biology (pmc.ncbi.nlm.nih.gov).

Oligomerization and lipid rafts: A hallmark of stomatin is its tendency to form homo-oligomers and associate with cholesterol-rich lipid rafts in the membrane (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In RBCs and other cells, stomatin molecules assemble into large complexes that are resistant to detergent, indicating raft association (pmc.ncbi.nlm.nih.gov). Breakthrough structural studies in 2025 resolved the cryo-EM structure of human stomatin in membranes, revealing a 16-subunit ring-shaped complex ~12 nm in diameter (pmc.ncbi.nlm.nih.gov). This ring forms a cage-like microdomain in the membrane that is mechanically distinct and resistant to curvature (pmc.ncbi.nlm.nih.gov). Such an arrangement suggests stomatin can stiffen the local membrane area, consistent with the idea that stomatin-rich rafts act as mechanotransduction platforms (pmc.ncbi.nlm.nih.gov). (Notably, other stomatin-family proteins like podocin and STOML3 similarly oligomerize and influence membrane stiffness in mechanosensory cells (pmc.ncbi.nlm.nih.gov).) Early biochemical work also indicated that stomatin is palmitoylated and partitions into raft fractions along with other major raft proteins (such as flotillins) (pmc.ncbi.nlm.nih.gov), although the recent structural data did not find a permanent cholesterol-binding pocket in stomatin’s structure (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Together, these features classify stomatin as a membrane scaffolding protein that organizes specialized lipid domains.

Localization: Stomatin is primarily localized to the plasma membrane, on the cytoplasmic side, where it clusters into discrete patches corresponding to lipid rafts (pmc.ncbi.nlm.nih.gov). In human RBCs, it is one of the major membrane proteins (~2–5% of total membrane protein) and is especially enriched in raft regions (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Stomatin has also been observed in intracellular vesicles and is notably enriched in exosomes. In fact, stomatin’s consistent presence in exosomes from many cell types (including blood cells and cancer cells) has led to proposals of using it as an exosomal marker (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). This enrichment likely ties to its raft-partitioning property, since several raft-organizing proteins (e.g., flotillin-1/2, caveolin-1) tend to be packaged into exosomes (pubmed.ncbi.nlm.nih.gov). Stomatin can also interact with other SPFH-family members to traffic within the cell; for example, stomatin-like protein 1 (STOML1) binds stomatin and targets to late endosomes (pmc.ncbi.nlm.nih.gov), though stomatin itself predominantly resides at the cell surface under steady-state conditions.

Membrane Scaffold and Protein Interactions

One of stomatin’s primary functions is to serve as a membrane scaffold or adaptor, organizing and modulating the activity of various membrane proteins. Stomatin exists as homo-oligomers in the membrane and can form complexes with a range of ion channels and transporters (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). A 2013 proteomic analysis of chemically cross-linked RBC membranes provided a clear picture of stomatin’s interactome in erythrocytes. The study identified GLUT1 (glucose transporter 1), band 3 anion exchanger (AE1), and aquaporin-1 as the major proteins cross-linked to stomatin, alongside several others such as the urea transporter (UT-B/SLC14A1), nucleoside transporter (ENT1/SLC29A1), plasma membrane Ca²⁺-ATPase (PMCA4), ferroportin (SLC40A1), CD47, and flotillin-1/2 (pmc.ncbi.nlm.nih.gov). These findings strongly support the idea that stomatin organizes multi-protein complexes in lipid rafts and influences the function of transport proteins in its vicinity (pmc.ncbi.nlm.nih.gov). Stomatin itself does not have known enzymatic activity – instead, it modulates other proteins’ activities through direct or indirect interactions, likely by affecting their localization, stability, or conformational state.

Regulation of transporter function: In erythrocytes, stomatin’s interaction with GLUT1 has a remarkable effect on substrate flux. Stomatin binding appears to alter GLUT1’s substrate specificity, diverting it from transporting glucose to transporting dehydroascorbic acid (DHA) – the oxidized form of vitamin C (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This was shown in species (like humans) that cannot synthesize vitamin C: stomatin helps convert GLUT1 into a high-affinity DHA importer, enabling efficient vitamin C uptake and recycling in RBCs (pmc.ncbi.nlm.nih.gov). As a result, stomatin-rich RBCs take up oxidized vitamin C from plasma and reduce it internally, a critical process for antioxidant maintenance in humans (pmc.ncbi.nlm.nih.gov). Concomitantly, stomatin presence was found to repress glucose uptake through GLUT1 in RBCs while enhancing DHA uptake (pmc.ncbi.nlm.nih.gov). The molecular mechanism is still under investigation, but this functional switch has been documented and links stomatin to metabolic adaptation in erythrocytes (pmc.ncbi.nlm.nih.gov).

Stomatin also modulates transporter activity in other cell types. In hepatocytes, stomatin has been shown to interact with the sodium taurocholate cotransporting polypeptide (NTCP/SLC10A1) – the bile acid uptake transporter – within raft microdomains (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Co-immunoprecipitation experiments confirmed stomatin–NTCP binding, and functional assays demonstrated that knocking down stomatin leads to increased bile salt uptake via NTCP (pubmed.ncbi.nlm.nih.gov). Interestingly, stomatin depletion raised NTCP levels at the cell surface, suggesting that stomatin normally limits NTCP’s plasma membrane abundance or activity (pubmed.ncbi.nlm.nih.gov). This indicates a negative regulatory role where stomatin keeps bile acid import in check, possibly by organizing NTCP in specific membrane domains or affecting its endocytic recycling. Such regulatory interactions underscore stomatin’s broader role as a modulator of solute transport across membranes.

Ion channel modulation and mechanosensation: Stomatin and its homologs are well known to influence ion channel function, particularly mechanosensitive and acid-sensing channels. In sensory neurons, stomatin is part of a protein complex (including stomatin-like proteins) that associates with acid-sensing ion channels (ASICs) and other degenerin/ENaC family channels (pmc.ncbi.nlm.nih.gov). Mammalian stomatin can bind ASIC subunits; notably, experiments have shown that stomatin must form dimers or higher-order oligomers to exert an inhibitory effect on ASIC currents (pmc.ncbi.nlm.nih.gov). For example, co-expression of stomatin was found to reduce ASIC3-mediated cation currents, and mutational studies revealed that stomatin monomers alone bind ASICs but dimerization is required for channel gating modulation (pmc.ncbi.nlm.nih.gov). These findings align with a 2012 study where a stomatin dimer was seen to modulate ASIC activity in vitro (pmc.ncbi.nlm.nih.gov). Beyond ASICs, stomatin-family proteins are integral to mechanosensory apparatus: Stomatin-like protein 3 (STOML3) is essential for touch sensation in mice, as it modulates mechanotransducer channels in dorsal root ganglion neurons (pmc.ncbi.nlm.nih.gov). In C. elegans, the stomatin homolog MEC-2 is required for mechanosensitive channel function in touch receptor neurons (pmc.ncbi.nlm.nih.gov). Recent research (2023) in worm neurons showed that MEC-2 forms dynamic protein condensates at the membrane that transition from liquid-like to a more solid state, a change that correlates with switching the complex’s function from cargo transport to mechanical signal transduction (phys.org) (phys.org). This highlights a general mechanism whereby stomatin proteins oligomerize to tune membrane mechanics and ion channel activity, impacting how cells sense mechanical forces. While stomatin (STOM) in humans is not the only player in touch sensation (redundant family members like STOML3 take on specialized roles), it clearly participates in ion channel regulation in various contexts.

A striking example in mechanosensation is in red blood cells themselves. RBCs experience shear stress in circulation and rely on mechanosensitive channels for volume regulation. Pannexin 1 (PANX1), a mechanosensitive membrane channel, was recently found to associate with stomatin in RBCs (www.mdpi.com). Proximity ligation assays showed that stomatin and PANX1 lie in close nanometer proximity on the erythrocyte membrane (www.mdpi.com). When stomatin is absent – as in RBCs from OHSt patients – PANX1 channel activity is dysregulated, supporting the idea that stomatin normally restrains or organizes PANX1 function (www.mdpi.com). Indeed, stomatin-deficient OHSt red cells exhibit a pathological leak of Na^+ and K^+ ions (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The loss of stomatin causes an unregulated cation flux and osmotic fragility in these cells (pmc.ncbi.nlm.nih.gov). Thus, stomatin is thought to stabilize ion channels or transporters in a closed/inactive state under resting conditions, preventing detrimental leaks. The pathophysiology of hereditary stomatocytosis underscores stomatin’s role: in the OHSt subtype, mutations in the Rh-associated glycoprotein (RhAG) lead to mis-trafficking of stomatin, its absence from RBC membranes, and consequent Na^+/K^+ leakage (pmc.ncbi.nlm.nih.gov). Another rare variant called stomatin-deficient cryohydrocytosis (sdCHC) is caused by GLUT1 mutations and likewise results in RBCs with no stomatin and extreme cation permeability, alongside neurological symptoms (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These disease connections illustrate that stomatin is crucial for maintaining membrane permeability barriers and ion homeostasis in red cells, likely through its interactions with transporters and channels.

Biological Roles and Pathways

Erythrocyte physiology: In human erythrocytes, stomatin constitutes ~2–3% of the membrane protein and is a key structural element of the membrane skeleton and raft domains (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Although stomatin is not required for RBC viability in mice (Stom knockout mice are viable and do not show obvious stomatocytosis (pmc.ncbi.nlm.nih.gov)), human RBCs lacking stomatin (in OHSt or sdCHC patients) have significant defects in volume regulation and membrane stability (pmc.ncbi.nlm.nih.gov). Stomatin is thought to organize a sub-membranous network by linking to the actin-spectrin cytoskeleton – early microscopy showed stomatin co-localizes with cortical actin filaments in some cells (pmc.ncbi.nlm.nih.gov). However, no direct actin-binding sequence has been confirmed in stomatin, and this remains an area of investigation (pmc.ncbi.nlm.nih.gov). The prevailing model is that stomatin-rich lipid rafts provide platforms to concentrate and regulate membrane transporters (like band 3, GLUT1, aquaporin, etc.) and to possibly sequester ion channels. By doing so, stomatin helps the RBC adapt to stresses: for instance, during oxidative stress, the stomatin-GLUT1 switch to vitamin C uptake helps protect RBCs (pmc.ncbi.nlm.nih.gov); during mechanical stress, stomatin may modulate stretch-activated channels (such as PANX1 or Piezo-type channels) to prevent undue ion leakage (www.mdpi.com). Stomatin also leaves reticulocytes via exosomes during RBC maturation in some species, in parallel with other membrane proteins (pmc.ncbi.nlm.nih.gov) – this regulated removal may fine-tune the final content of the mature red cell membrane. Overall, stomatin’s primary role in RBCs is structural and regulatory, ensuring proper membrane composition, fluidity, and transporter function for a durable, biconcave cell (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Signal transduction and metabolic pathways: Beyond RBCs, stomatin has emerging roles in cell signaling and metabolism. A recent Nature Communications (2022) study demonstrated that stomatin influences adipogenesis (fat cell differentiation) through the ERK/MAPK signaling pathway (pmc.ncbi.nlm.nih.gov). Stomatin is highly expressed in adipocyte lipid rafts, and its expression increases when pre-adipocytes are induced to differentiate or when mice are fed a high-fat diet (pmc.ncbi.nlm.nih.gov). Functional assays showed that overexpression of stomatin enhances lipid droplet growth (by promoting droplet fusion) and fatty acid uptake in maturing adipocytes (pmc.ncbi.nlm.nih.gov). Conversely, stomatin knockdown impaired the normal induction of key adipogenic transcription factors (such as C/EBPβ and PPARγ) and led to smaller adipocytes with less lipid storage (pmc.ncbi.nlm.nih.gov). Mechanistically, stomatin was found to modulate the activity of the ERK pathway during differentiation – loss of stomatin resulted in altered phosphorylation dynamics of ERK1/2, which are crucial for adipogenesis (pubmed.ncbi.nlm.nih.gov). These findings position stomatin as a positive regulator of adipocyte maturation, linking membrane microdomain organization to intracellular signaling cascades. It appears that by scaffolding certain raft proteins (possibly insulin or growth factor receptors, or downstream effectors), stomatin can influence the ERK pathway and thereby the gene expression program of differentiation (pmc.ncbi.nlm.nih.gov).

Stomatin’s impact on signaling is also evident in other contexts. In the liver, as noted, stomatin modulates bile acid signaling by regulating NTCP-mediated bile uptake – which could have downstream effects on metabolic homeostasis and even viral entry (since NTCP is the entry receptor for hepatitis B/D viruses) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). There is also evidence that stomatin can interact with signaling molecules or adaptors. A proteomic study in macrophages (2023) found that stomatin binds to peroxiredoxin-1 (Prdx1), a redox-regulating enzyme, and targets it for lysosomal degradation (pubmed.ncbi.nlm.nih.gov). By promoting Prdx1 turnover, stomatin caused an increase in cellular reactive oxygen species (ROS) levels, which in turn enhanced NF-κB signaling and osteoclast differentiation (pubmed.ncbi.nlm.nih.gov). This was shown in the context of bone metabolism: stomatin expression was upregulated in osteoclast precursors from osteoporotic bone, and mice lacking stomatin had increased bone mass due to reduced osteoclast activity (pubmed.ncbi.nlm.nih.gov). Importantly, inhibiting stomatin in macrophage/osteoclast-lineage cells blunted osteoclastogenesis and protected mice from estrogen-withdrawal bone loss (pubmed.ncbi.nlm.nih.gov). These results reveal a novel role for stomatin in a ROS-mediated signaling pathway that drives cell differentiation (osteoclast formation). It reinforces the concept that stomatin’s scaffold function is not limited to ion transporters – it can extend to organizing signal-regulatory complexes (in this case, a Prdx1 degradation complex) at the membrane or cytosolic face, thereby influencing pathways like oxidative signaling and NF-κB.

Pathophysiological and clinical significance: While stomatin is ubiquitously expressed, its dysregulation can have tissue-specific consequences. In the hematological realm, stomatin levels serve as a diagnostic marker for certain hereditary anemias (OHSt and cryohydrocytosis) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In those disorders, absence of stomatin in RBC membranes is a hallmark finding, used to distinguish them from other hemolytic anemias. Interestingly, the causative mutations in these conditions lie in other genes (ion channels or transporters), suggesting stomatin loss is a downstream effect that exacerbates the membrane leak phenotype (pmc.ncbi.nlm.nih.gov). The “stomatin-deficient” phenotype in anemic patients highlights how crucial stomatin is for normal RBC function.

Emerging evidence links stomatin to cancer and other diseases, mostly through its regulatory effects on signaling pathways. For instance, low stomatin expression has been correlated with increased metastasis in some cancers such as non-small cell lung cancer, implying a tumor suppressor function (possibly by restraining pro-migratory signaling at the membrane) (www.spandidos-publications.com). In contrast, high stomatin levels in certain lymphoma subtypes were associated with worse prognosis, suggesting context-dependent effects (pmc.ncbi.nlm.nih.gov). Experimentally, overexpressing stomatin in cancer cell lines was reported to inhibit the Akt signaling axis and slow tumor growth, supporting a role in modulating growth factor signaling at lipid rafts (pubmed.ncbi.nlm.nih.gov). These findings are still preliminary, but they dovetail with the idea that stomatin-rich microdomains influence signaling pathways like Akt and ERK that are central to proliferation and survival. Given its involvement in multiple pathways, stomatin (and its binding partners) could be explored as therapeutic targets. The osteoporosis study mentioned above is a prime example – by targeting stomatin in certain cells, researchers achieved a beneficial modulation of cell function (reducing osteoclast activity) (pubmed.ncbi.nlm.nih.gov). Similarly, manipulating stomatin levels could potentially alter metabolic outcomes in obesity or modulate viral entry in hepatitis (via NTCP interaction), though such applications remain to be tested.

Conclusion

Stomatin (STOM) is now recognized as a multifaceted membrane organizer that influences cell physiology by shaping the lipid microenvironment and regulating membrane protein function. Its primary role is structural and regulatory: forming membrane microdomains (rafts) and scaffolding select channels and transporters, thereby tuning their activity. In human cells, stomatin helps control substrate transport (glucose, vitamin C, bile acids), ion flux (Na^+, K^+, etc.), and mechanosensitive signaling, all dependent on context. These specific functions are carried out at the cytoplasmic face of the plasma membrane, often in cholesterol-rich domains where stomatin oligomers reside (pmc.ncbi.nlm.nih.gov) (www.mdpi.com). From red blood cells ensuring osmotic stability, to neurons modulating mechano‐transducers, to adipocytes expanding lipid stores, stomatin’s influence is widespread but consistently centers on organizing membrane components to facilitate the appropriate physiological response.

Mechanistically, stomatin does not act as an enzyme or classic receptor; rather, it is an adaptor protein – it binds to proteins like GLUT1, ASIC channels, or NTCP and alters their localization or function through direct interaction or by altering the local membrane properties (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The biological significance of stomatin is evident from both evolutionary conservation and disease associations. Loss of stomatin from the membrane can lead to dramatic phenotypes (ion-leaky, fragile RBCs (pmc.ncbi.nlm.nih.gov), impaired mechanosensation (pmc.ncbi.nlm.nih.gov), or altered cell differentiation (pubmed.ncbi.nlm.nih.gov)), whereas proper stomatin function contributes to homeostasis (e.g. vitamin C recycling in humans via RBCs (pmc.ncbi.nlm.nih.gov)). Ongoing research (2022–2024) continues to uncover new roles, such as stomatin’s control of MAPK signaling in adipogenesis (pmc.ncbi.nlm.nih.gov) and its impact on osteoclast biology through ROS signaling (pubmed.ncbi.nlm.nih.gov). These studies not only deepen our understanding of how stomatin works at the molecular level, but also point to potential translational avenues – for example, targeting stomatin-rich lipid raft complexes could modulate immune cell activity or metabolic processes in disease. In summary, stomatin serves as a key structural regulator of cell membranes, orchestrating the interplay between membrane structure and function to support proper cellular physiology.

References: (Key references from recent literature are cited in-line above, with publication year and source when available)

Citations

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27. AnnotationURLCitation(end_index=8813, start_index=8651, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=molecular%2C%20cross,scaffolding%20protein%20modulating%20transport%20proteins')
28. AnnotationURLCitation(end_index=9530, start_index=9361, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Apparently%2C%20stomatin%20modulates%20GLUT1%20to,is%20implicated%20that%20the%20high')
29. AnnotationURLCitation(end_index=9673, start_index=9531, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=match%20at%20L620%20unable%20to,Hagen%20et%20al.%2C%202008')
30. AnnotationURLCitation(end_index=10013, start_index=9871, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=match%20at%20L620%20unable%20to,Hagen%20et%20al.%2C%202008')
31. AnnotationURLCitation(end_index=10338, start_index=10169, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Apparently%2C%20stomatin%20modulates%20GLUT1%20to,is%20implicated%20that%20the%20high')
32. AnnotationURLCitation(end_index=10631, start_index=10462, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Apparently%2C%20stomatin%20modulates%20GLUT1%20to,is%20implicated%20that%20the%20high')
33. AnnotationURLCitation(end_index=10962, start_index=10793, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Apparently%2C%20stomatin%20modulates%20GLUT1%20to,is%20implicated%20that%20the%20high')
34. AnnotationURLCitation(end_index=11396, start_index=11221, title='The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32316189/#:~:text=The%20sodium%20taurocholate%20cotransporting%20polypeptide,rafts%2C%20as%20demonstrated%20by%20a')
35. AnnotationURLCitation(end_index=11549, start_index=11397, title='The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32316189/#:~:text=play%20a%20role%20in%20the,CLCC1%20overexpression%20nor%20its%20knockdown')
36. AnnotationURLCitation(end_index=11888, start_index=11731, title='The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32316189/#:~:text=knockdown%20increased%20NTCP,interaction%20modulates%20bile%20salt%20transport')
37. AnnotationURLCitation(end_index=12207, start_index=12050, title='The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32316189/#:~:text=knockdown%20increased%20NTCP,interaction%20modulates%20bile%20salt%20transport')
38. AnnotationURLCitation(end_index=13072, start_index=12891, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Mammalian%20stomatin%20modulates%20ENaC,mediated%20currents%20%5B23%5D.%20Similarly%2C%20stomatin')
39. AnnotationURLCitation(end_index=13438, start_index=13257, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Mammalian%20stomatin%20modulates%20ENaC,mediated%20currents%20%5B23%5D.%20Similarly%2C%20stomatin')
40. AnnotationURLCitation(end_index=13847, start_index=13666, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Mammalian%20stomatin%20modulates%20ENaC,mediated%20currents%20%5B23%5D.%20Similarly%2C%20stomatin')
41. AnnotationURLCitation(end_index=14069, start_index=13955, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Kozlenkov%20A,Google%20Scholar')
42. AnnotationURLCitation(end_index=14473, start_index=14306, title='Structural basis for membrane microdomain formation by a human Stomatin complex - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12344292/#:~:text=Several%20members%20of%20the%20stomatin,analysis%20of%20human%20Stomatin%20reveals')
43. AnnotationURLCitation(end_index=14766, start_index=14599, title='Structural basis for membrane microdomain formation by a human Stomatin complex - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12344292/#:~:text=Several%20members%20of%20the%20stomatin,analysis%20of%20human%20Stomatin%20reveals')
44. AnnotationURLCitation(end_index=15238, start_index=15053, title='A change in rigidity switches the function of protein condensates involved in sensing touch', type='url_citation', url='https://phys.org/news/2023-10-rigidity-function-protein-condensates-involved.html#:~:text=The%20focus%20of%20the%20study,Caenorhabditis%20elegans%2C%20a%20model%20organism')
45. AnnotationURLCitation(end_index=15409, start_index=15239, title='A change in rigidity switches the function of protein condensates involved in sensing touch', type='url_citation', url='https://phys.org/news/2023-10-rigidity-function-protein-condensates-involved.html#:~:text=promoting%20MEC,of%20mechanical%20cues%20during%20mechanosensation')
46. AnnotationURLCitation(end_index=16245, start_index=16100, title='Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells', type='url_citation', url='https://www.mdpi.com/1422-0067/23/16/9401#:~:text=modulate%20bile%20salt%20uptake%20,lipid%20rafts%2C%20with%20connections%20to')
47. AnnotationURLCitation(end_index=16498, start_index=16365, title='Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells', type='url_citation', url='https://www.mdpi.com/1422-0067/23/16/9401#:~:text=Proximity%20Ligation%20Assay%20,Finally%2C%20we%20confirmed%20our')
48. AnnotationURLCitation(end_index=16824, start_index=16679, title='Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells', type='url_citation', url='https://www.mdpi.com/1422-0067/23/16/9401#:~:text=modulate%20bile%20salt%20uptake%20,lipid%20rafts%2C%20with%20connections%20to')
49. AnnotationURLCitation(end_index=17104, start_index=16917, title='Hereditary dehydrated and overhydrated stomatocytosis: recent advances - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10088641/#:~:text=The%20hereditary%20stomatocytoses%20and%20allied,stomatocytosis%20and%20familial%20pseudohyperkalemia%2C%20a')
50. AnnotationURLCitation(end_index=17263, start_index=17105, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=the%20very%20rare%20condition%2C%20stomatin,spanning%20membrane%20proteins')
51. AnnotationURLCitation(end_index=17490, start_index=17361, title='Erythrocyte adducin: A structural regulator of the red blood cell membrane - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3385930/#:~:text=,increased%20cation%20fluxes%20and%20elevated')
52. AnnotationURLCitation(end_index=18060, start_index=17898, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=investigation%20revealed%20that%20stomatin%20deficiency,sdCHC%2C%20see%20below')
53. AnnotationURLCitation(end_index=18432, start_index=18274, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=the%20very%20rare%20condition%2C%20stomatin,spanning%20membrane%20proteins')
54. AnnotationURLCitation(end_index=18568, start_index=18433, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=Stomatin,hematological%20symptoms%20that%20do%20not')
55. AnnotationURLCitation(end_index=19175, start_index=18992, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=The%20widely%20expressed%2C%20homo,subsequent%20purification%20by%20immunoaffinity%20chromatography')
56. AnnotationURLCitation(end_index=19304, start_index=19176, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=Cross,probably%20acts%20as%20a%20scaffolding')
57. AnnotationURLCitation(end_index=19596, start_index=19436, title='Structure-function analysis of human stomatin: A mutation study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5456319/#:~:text=of%20this%20protein%20in%20red,due%20to%20mistrafficking%20during%20terminal')
58. AnnotationURLCitation(end_index=19853, start_index=19724, title='Erythrocyte adducin: A structural regulator of the red blood cell membrane - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3385930/#:~:text=,increased%20cation%20fluxes%20and%20elevated')
59. AnnotationURLCitation(end_index=20199, start_index=20050, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=human%20erythrocyte%20membrane%20domains%20,binding%20domain%20of')
60. AnnotationURLCitation(end_index=20450, start_index=20317, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=The%20precise%20role%20of%20stomatin,In%20species')
61. AnnotationURLCitation(end_index=20954, start_index=20812, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=match%20at%20L620%20unable%20to,Hagen%20et%20al.%2C%202008')
62. AnnotationURLCitation(end_index=21244, start_index=21099, title='Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells', type='url_citation', url='https://www.mdpi.com/1422-0067/23/16/9401#:~:text=modulate%20bile%20salt%20uptake%20,lipid%20rafts%2C%20with%20connections%20to')
63. AnnotationURLCitation(end_index=21474, start_index=21374, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=al,0030%20%5BDOI')
64. AnnotationURLCitation(end_index=21876, start_index=21743, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=The%20precise%20role%20of%20stomatin,In%20species')
65. AnnotationURLCitation(end_index=22005, start_index=21877, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=Cross,probably%20acts%20as%20a%20scaffolding')
66. AnnotationURLCitation(end_index=22440, start_index=22300, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9296665/#:~:text=hypertrophy%20and%20obesity,It%20also%20promotes%20fatty')
67. AnnotationURLCitation(end_index=22714, start_index=22612, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9296665/#:~:text=assay%20%28Fig,BAT')
68. AnnotationURLCitation(end_index=23022, start_index=22882, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9296665/#:~:text=hypertrophy%20and%20obesity,It%20also%20promotes%20fatty')
69. AnnotationURLCitation(end_index=23328, start_index=23206, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9296665/#:~:text=match%20at%20L601%20respectively%29,7c')
70. AnnotationURLCitation(end_index=23680, start_index=23543, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/35854007/#:~:text=acid%20uptake%20and%20lipid%20droplet,PR%29%2C%20and%20BAT')
71. AnnotationURLCitation(end_index=24210, start_index=24070, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9296665/#:~:text=hypertrophy%20and%20obesity,It%20also%20promotes%20fatty')
72. AnnotationURLCitation(end_index=24703, start_index=24528, title='The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32316189/#:~:text=The%20sodium%20taurocholate%20cotransporting%20polypeptide,rafts%2C%20as%20demonstrated%20by%20a')
73. AnnotationURLCitation(end_index=24861, start_index=24704, title='The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32316189/#:~:text=knockdown%20increased%20NTCP,interaction%20modulates%20bile%20salt%20transport')
74. AnnotationURLCitation(end_index=25284, start_index=25117, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Mechanistically%2C%20STOM%20interacts%20with%20Prdx1%2C,induced%20bone%20loss.%20Overall')
75. AnnotationURLCitation(end_index=25634, start_index=25467, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Mechanistically%2C%20STOM%20interacts%20with%20Prdx1%2C,induced%20bone%20loss.%20Overall')
76. AnnotationURLCitation(end_index=26027, start_index=25860, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Osteoporosis%20is%20a%20metabolic%20bone,normal%20conditions%20and%20after%20ovariectomy')
77. AnnotationURLCitation(end_index=26349, start_index=26182, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Mechanistically%2C%20STOM%20interacts%20with%20Prdx1%2C,induced%20bone%20loss.%20Overall')
78. AnnotationURLCitation(end_index=27246, start_index=27079, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=Stomatin%20first%20attracted%20attention%20when,was%20named%20after%20the%20disease')
79. AnnotationURLCitation(end_index=27409, start_index=27247, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=investigation%20revealed%20that%20stomatin%20deficiency,sdCHC%2C%20see%20below')
80. AnnotationURLCitation(end_index=27913, start_index=27751, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=investigation%20revealed%20that%20stomatin%20deficiency,sdCHC%2C%20see%20below')
81. AnnotationURLCitation(end_index=28548, start_index=28398, title='Experimental and Therapeutic Medicine', type='url_citation', url='https://www.spandidos-publications.com/10.3892/etm.2021.10992#:~:text=7%20,activity%20of%20the%20anion%20exchanger')
82. AnnotationURLCitation(end_index=28836, start_index=28688, title='Upregulation of stomatin is associated with poor prognosis and promotes tumor progression of orbital diffuse large B-cell lymphoma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12141002/#:~:text=Upregulation%20of%20stomatin%20is%20associated,Google%20Scholar')
83. AnnotationURLCitation(end_index=29158, start_index=29040, title='Stomatin-Mediated Inhibition of the Akt Signaling Axis Suppresses Tumor Growth - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/33757977/#:~:text=Stomatin,Cancer%20Chemother%20Pharmacol')
84. AnnotationURLCitation(end_index=29842, start_index=29675, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Mechanistically%2C%20STOM%20interacts%20with%20Prdx1%2C,induced%20bone%20loss.%20Overall')
85. AnnotationURLCitation(end_index=30946, start_index=30763, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=The%20widely%20expressed%2C%20homo,subsequent%20purification%20by%20immunoaffinity%20chromatography')
86. AnnotationURLCitation(end_index=31092, start_index=30947, title='Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells', type='url_citation', url='https://www.mdpi.com/1422-0067/23/16/9401#:~:text=modulate%20bile%20salt%20uptake%20,lipid%20rafts%2C%20with%20connections%20to')
87. AnnotationURLCitation(end_index=31818, start_index=31656, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=molecular%2C%20cross,scaffolding%20protein%20modulating%20transport%20proteins')
88. AnnotationURLCitation(end_index=32000, start_index=31819, title='Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3790964/#:~:text=Mammalian%20stomatin%20modulates%20ENaC,mediated%20currents%20%5B23%5D.%20Similarly%2C%20stomatin')
89. AnnotationURLCitation(end_index=32340, start_index=32211, title='Erythrocyte adducin: A structural regulator of the red blood cell membrane - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3385930/#:~:text=,increased%20cation%20fluxes%20and%20elevated')
90. AnnotationURLCitation(end_index=32535, start_index=32368, title='Structural basis for membrane microdomain formation by a human Stomatin complex - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12344292/#:~:text=Several%20members%20of%20the%20stomatin,analysis%20of%20human%20Stomatin%20reveals')
91. AnnotationURLCitation(end_index=32736, start_index=32569, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Osteoporosis%20is%20a%20metabolic%20bone,normal%20conditions%20and%20after%20ovariectomy')
92. AnnotationURLCitation(end_index=32986, start_index=32844, title='The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5911802/#:~:text=match%20at%20L620%20unable%20to,Hagen%20et%20al.%2C%202008')
93. AnnotationURLCitation(end_index=33251, start_index=33111, title='Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9296665/#:~:text=hypertrophy%20and%20obesity,It%20also%20promotes%20fatty')
94. AnnotationURLCitation(end_index=33478, start_index=33311, title='Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40595453/#:~:text=Mechanistically%2C%20STOM%20interacts%20with%20Prdx1%2C,induced%20bone%20loss.%20Overall')