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8.A.21 The Stomatin/Podocin/Band 7/Nephrosis.2/SPFH (Stomatin) Family

Stomatin (STOM) is one of the major integral membrane proteins of the human erythrocyte (Band 7.2b), and its absence is associated with the hemolytic anemia condition known as hereditary stomatocytosis (hydrocytosis). Stomatin is thought to function as a negative regulator of univalent cation permeability. Its homologues are found in almost all species of eukaryotes, bacteria and archaea. In many prokaryotes the stomatin-encoding genes are in bicistronic operons that also encode integral membrane proteases with one N-terminal TMS, an N-terminal ClpP-type serine endoprotease domain, and a C-terminal 6 TMS hydrophobic domain. The proteases cleave the C-terminal hydrophobic regions in the stomatin homologue (Yokoyama and Matsui, 2005). The cleavage of the stomatin homologue by the protease may cause an ion channel to open. The erythrocyte stomatin may have 3 TMSs, one very hydrophobic TMS (residues 27-51), and two moderately hydrophobic TMSs (residues 78-94 and 265-282) in this 288 aa protein. The Mec2 protein of C. elegans is a subunit in the touch responsive mechanosensitive degenerin channel complex in the ENaC family (TC #1.A.6.2.2). Stomatins are monotopic integral membrane proteins found in all classes of life that regulate members of the acid-sensing ion channel (ASIC) family (TC# 1.A.6). Regulation requires two distinct sites on ASIC3: the distal C-terminus and the first TMS1. The C-terminal site is critical for formation of the STOM-ASIC3 complex, while TMS1 is required only for the regulatory effect (Klipp et al. 2020).

Human erythrocytes express the highest level of the Glut1 glucose transporter (TC# 2.A.1.1.28). Glucose transport decreases during human erythropoiesis despite a >3-log increase in Glut1 transcripts. Glut1-mediated transport of L-dehydroascorbic acid (DHA), an oxidized form of ascorbic acid (AA), is dramatically enhanced. Stomatin, regulates the switch from glucose to DHA transport (Montel-Hagen et al., 2008). Erythrocyte Glut1 and associated DHA uptake are unique traits of humans and the few other mammals that have lost the ability to synthesize AA from glucose. Mice, a species capable of synthesizing AA, express Glut4 but not Glut1 in mature erythrocytes. Thus, erythrocyte-specific coexpression of Glut1 with stomatin constitutes a compensatory mechanism in mammals that are unable to synthesize vitamin C.

Nephrotic syndrome (NS) is manifested by hyperproteinuria, hypoalbuminemia, and edema. The NPHS2 gene that encodes podocin has the most mutations among the genes that are involved in the pathophysiology of NS. Podocin is expressed exclusively in podocytes and is localized to the slit-diaphragm (SD). Mutations in podocin are associated with steroid-resistant NS and rapid progression to end-stage renal disease, thus signifying its role in maintaining SD integrity. Mulukala et al. 2016 deduced a model for human podocin, discussed the details of transmembrane localization and intrinsically unstrucMembrane fusions that occur during vesicle transport, virus infection, and tissue development, involve receptors that mediate membrane contact and initiate fusion and effectors that execute membrane reorganization and fusion pore formation. Some of these ftured regions, and provided an understanding of how podocin interacts with other SD components. 

Some fusogenic receptors/effectors are preferentially recruited to lipid raft membrane microdomains, and stomatin is a major constituents of lipid rafts (Lee et al. 2016).  Cells expressing more stomatin or exposed to exogenous stomatin are more prone to undergoing cell fusion. During osteoclastogenesis, depletion of stomatin inhibits cell fusion, and in stomatin transgenic mice, increased cell fusion leading to enhanced bone resorption and subsequent osteoporosis were observed. With its unique molecular topology, stomatin forms molecular assembly within lipid rafts or on the appositional plasma membranes, and promotes membrane fusion by modulating fusogenic protein engagement (Lee et al. 2016).

Bacteria have homologues that appear to play roles in membrane stress adaptation (Akiyama 2009).

This family belongs to the: Stomatin/Erlin/Podicin Superfamily.

References associated with 8.A.21 family:

Akiyama, Y. (2009). Quality control of cytoplasmic membrane proteins in Escherichia coli. J Biochem 146: 449-454. 19454621
Cheng, L., S. Zhang, F. Shang, Y. Ning, Z. Huang, R. He, J. Sun, and S. Dong. (2021). Emodin Improves Glucose and Lipid Metabolism Disorders in Obese Mice Activating Brown Adipose Tissue and Inducing Browning of White Adipose Tissue. Front Endocrinol (Lausanne) 12: 618037. 34040579
Coates, P.J., R. Nenutil, A. McGregor, S.M. Picksley, D.H. Crouch, P.A. Hall, and E.G. Wright. (2001). Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence. Exp Cell Res 265: 262-273. 11302691
Hu, J., Y. Gao, Q. Huang, Y. Wang, X. Mo, P. Wang, Y. Zhang, C. Xie, D. Li, and J. Yao. (2021). Flotillin-1 Interacts With and Sustains the Surface Levels of TRPV2 Channel. Front Cell Dev Biol 9: 634160. 33634132
Klipp, R.C., M.M. Cullinan, and J.R. Bankston. (2020). Insights into the molecular mechanisms underlying the inhibition of acid-sensing ion channel 3 gating by stomatin. J Gen Physiol 152:. 32012213
Lang, D.M., S. Lommel, M. Jung, R. Ankerhold, B. Petrausch, U. Laessing, M.F. Wiechers, H. Plattner, and C.A. Stuermer. (1998). Identification of reggie-1 and reggie-2 as plasmamembrane-associated proteins which cocluster with activated GPI-anchored cell adhesion molecules in non-caveolar micropatches in neurons. J Neurobiol 37: 502-523. 9858255
Lapatsina, L., J.A. Jira, E.S. Smith, K. Poole, A. Kozlenkov, D. Bilbao, G.R. Lewin, and P.A. Heppenstall. (2012). Regulation of ASIC channels by a stomatin/STOML3 complex located in a mobile vesicle pool in sensory neurons. Open Biol 2: 120096. 22773952
Lee, J.H., C.F. Hsieh, H.W. Liu, C.Y. Chen, S.C. Wu, T.W. Chen, C.S. Hsu, Y.H. Liao, C.Y. Yang, J.F. Shyu, W.B. Fischer, and C.H. Lin. (2016). Lipid raft-associated stomatin enhances cell fusion. FASEB J. [Epub: Ahead of Print] 27663861
Montel-Hagen, A., S. Kinet, N. Manel, C. Mongellaz, R. Prohaska, J.L. Battini, J. Delaunay, M. Sitbon, and N. Taylor. (2008). Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. Cell 132: 1039-1048. 18358815
Mulukala, S.K., R. Nishad, L.P. Kolligundla, M.A. Saleem, N.P. Prabhu, and A.K. Pasupulati. (2016). In silico Structural characterization of podocin and assessment of nephrotic syndrome-associated podocin mutants. IUBMB Life. [Epub: Ahead of Print] 27193387
Mulukala, S.K.N., S.S. Irukuvajjula, K. Kumar, K. Garai, P. Venkatesu, R. Vadrevu, and A.K. Pasupulati. (2020). Structural features and oligomeric nature of human podocin domain. Biochem Biophys Rep 23: 100774. 32617419
Nanatani, K., T. Ishii, A. Masuda, S. Katsube, T. Ando, H. Yoneyama, and K. Abe. (2022). Novel transporter screening technology for chemical production by microbial fermentation. J Gen Appl Microbiol. [Epub: Ahead of Print] 36567121
Planchon, D., E. Rios Morris, M. Genest, F. Comunale, S. Vacher, I. Bièche, E.V. Denisov, L.A. Tashireva, V.M. Perelmuter, S. Linder, P. Chavrier, S. Bodin, and C. Gauthier-Rouvière. (2018). MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins. J Cell Sci 131:. 30111578
Yan, X., Z. Zhao, J. Weaver, T. Sun, J.W. Yun, C.A. Roneker, F. Hu, N.M. Doliba, C.C.W. McCormick, M.Z. Vatamaniuk, and X.G. Lei. (2022). Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction. Redox Biol 56: 102457. 36063729
Yokoyama, H. and I. Matsui. (2005). A novel thermostable membrane protease forming an operon with a stomatin homolog from the hyperthermophilic archaebacterium Pyrococcus horikoshii. J. Biol. Chem. 280: 6588-6594. 15611110
Yu, X.M., X.D. Yu, Z.P. Qu, X.J. Huang, J. Guo, Q.M. Han, J. Zhao, L.L. Huang, and Z.S. Kang. (2008). Cloning of a putative hypersensitive induced reaction gene from wheat infected by stripe rust fungus. Gene 407: 193-198. 17980516