Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Subject Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Subject Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
UP FRONT MATTERSBrief Review
You have accessRestricted Access

Lipid–Protein Interactions along the Slit Diaphragm of Podocytes

Bernhard Schermer and Thomas Benzing
JASN March 2009, 20 (3) 473-478; DOI: https://doi.org/10.1681/ASN.2008070694
Bernhard Schermer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Benzing
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

Podocytes are visceral epithelial cells supporting the function of the glomerular filter. Interdigitating foot processes of podocytes enwrap the glomerular capillaries and are connected by a highly specialized cell junction, the slit diaphragm. Signal transduction at the slit diaphragm is essential for the proper function of the kidney filtration barrier. The slit diaphragm constitutes a dynamic multiprotein signaling complex that contains structural proteins, receptors, signaling adaptors, ion channels, and scaffolding proteins. Function of some of these proteins requires cholesterol attached to the multiprotein complex. Recruitment of cholesterol is achieved through the PHB domain protein podocin, a member of a novel family of lipid-binding proteins that are conserved through evolution. The finding that cholesterol interaction regulates the activity of ion channels at the glomerular filtration barrier has important implications for renal physiology and pathophysiology.

Human kidneys filter approximately 180 L/d plasma water. The glomerular filter through which ultrafiltrate passes consists of three layers: The fenestrated endothelium, the intervening glomerular basement membrane, and the slit diaphragms created by epithelial podocyte foot processes.1,2 Podocytes elaborate long, regularly spaced, interdigitated foot processes that enwrap the glomerular capillaries and form a 40-nm-wide filtration slit that is bridged by a continuous membrane-like cell junction called the slit diaphragm (Figure 1). The filtration barrier behaves as a selective sieve restricting the passage of macromolecules on the basis of their size, shape, and charge. A number of genes encoding for proteins localized to the slit diaphragm of podocytes have been identified in the past several years, and their mutations explain a growing number of genetic causes leading to hereditary nephrotic syndrome.3–10 Identification of these genes caused a lot of excitement that resulted in a great deal of focus on the critical role of slit diaphragm proteins in mediating signal transduction in the podocyte.11–14 These observations demonstrate that slit diaphragm signaling regulates podocyte cell differentiation, cytoskeletal dynamics, protein expression, and cell survival.15–22 Much insight into the signaling function of the slit diaphragm protein complex resulted from work on podocin, the slit diaphragm protein that is mutated in genetic forms of steroid-resistant nephrotic syndrome. Additional findings also suggest that slit diaphragm proteins form local lipid–protein supercomplexes involving an intriguing role for cholesterol in modulating cell signaling at the filtration slit.23

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

The glomerular filtration barrier consists of three layers: Fenestrated endothelial cells, the glomerular basement membrane, and processes of podocytes, which are connected through the slit diaphragm protein complex. (B, blood side; U, urinary space; F, foot process; SD, slit diaphragm; BM, basement membrane; E, endothelial cell.

PODOCIN AND CHOLESTEROL–AN AFFAIR TO REMEMBER1

The most common genetic form of hereditary nephrotic syndrome is a steroid-resistant disease caused by mutations in NPHS2, the gene encoding for podocin.3 Podocin localizes to the slit diaphragm of podocytes and interacts with the transmembrane adhesion protein nephrin. This interaction is required for efficient signaling through nephrin and its associated proteins.16 Podocin belongs to a large family of evolutionarily conserved membrane-associated proteins of previously unknown function.24,25 The PHB domain proteins constitute a family of more than 1300 proteins, all of which share an approximately 150–amino acid domain similar to that in the mitochondrial protein prohibitin (PHB domain24 or SPFH domain26). More than 360 of these proteins have been identified in animals, many of which have an N-terminal hydrophobic region, which places them on the inner leaflet of the lipid bilayer. On the basis of biochemical fractionation in detergent-resistant membrane preparations, a number of the mammalian PHB domain proteins co-fractionate with lipid rafts of the plasma and intracellular membranes24,26; however, until recently, the function of PHB domain proteins at the molecular level has remained unclear.

This situation has changed with the observation that podocin and related proteins can directly bind and recruit cholesterol.25 Binding of cholesterol requires the PHB domain and an adjacent small hydrophobic region of the protein that results in recruitment of cholesterol to the slit diaphragm multiprotein complex. Podocin does this by forming multimers as a high molecular weight protein complex that recruits cholesterol into this complex.18,23,27 Thus, by directly binding cholesterol on the membrane, multimerizing, and recruiting associated proteins, podocin contributes to the formation of a megadalton protein–lipid supercomplex.

Is lipid interaction important for the function of this complex? Cholesterol is not required for podocin multimerization23; formation of the megadalton complex is not affected by cholesterol depletion, and podocin mutants deficient in cholesterol binding are able to aggregate as large complexes; however, in vivo assays revealed that cholesterol binding is essential for the function of podocin-associated ion channels. Podocin binds and regulates the transient receptor potential (TRP) channel TRPC6 at the slit diaphragm.23 Consequently, mutations in either podocin or TRPC6 result in severe proteinuric kidney disease.3,6,8 The in vivo importance of cholesterol interactions is demonstrated by studies that introduced the nematode Caenorhabditis elegans as model organism to test the function of podocin-related proteins.23

The closest homologue of podocin in C. elegans is MEC-2.28,29 Podocin and MEC-2 share a similar structure with a central membrane-close hydrophobic region, amino and carboxy terminal tails facing the cytoplasm, and PHB domains that are 50% identical and 80% similar. Like podocin, MEC-2 is part of a multiprotein channel complex with the degenerin/epithelial Na+ channel proteins MEC-4 and MEC-10 that transduces gentle touch (Figure 2). In touch receptor neurons, the channel complex is localized to regular puncta along the neuronal process; MEC-2 regulates the MEC-4/MEC-10 ion channel in these puncta. C. elegans genes are also amenable to genetic manipulation. Moreover, MEC-2 function can be tested in vivo by analyzing responses of the worm to gentle touch with an eyelash attached to a toothpick; the worm responds by changing the direction of movement.30 The molecular function of podocin/MEC-2 in worms is amenable to testing with these assays: MEC-2, similar to podocin, binds and interacts with cholesterol. Mutational analysis revealed that cholesterol binding to MEC-2 is essential for the function of the MEC-2 ion channel complex but does not affect complex assembly or targeting. Touch sensation requires binding of cholesterol to the MEC-2 complex in vivo,23 and mutant worms expressing a MEC-2 protein that selectively lost the ability to bind and recruit cholesterol do not respond to touch. A special property of the nematode is its dietary requirement for cholesterol. C. elegans cannot synthesize sterols that can be used experimentally in cholesterol depletion assays. Feeding the worm cholesterol-free diets results in the loss of touch sensation. Similarly, cholesterol interaction of podocin is required for the podocin-mediated augmentation of TRPC6 current in oocytes and in cultured cells. In other words, MEC-2 and podocin bind and recruit cholesterol to organize the lipid microenvironment of the associated ion channel complexes that is essential for their function.25

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Podocin and MEC-2 are associated with similar proteins.

Cholesterol is a major component of mammalian cell membranes, where it changes the physicochemical properties of the lipid bilayer; however, C. elegans does not use sterols as a structural component of the membrane.31 This argues against the need for cholesterol as a structural membrane component but rather favors a primary role for sterols in the function of protein–lipid ion channel supercomplexes. The classic lipid raft hypothesis postulates lipid microdomains rich in cholesterol and glycosphingolipids, distinct liquid-ordered phases in the lipid bilayer, dispersed in a liquid-disordered matrix of unsaturated glycerolipids.32,33 Although novel data do not argue against the existence of these rafts, one does not have to invoke this classic lipid raft model to explain new findings: Multiprotein complexes based on PHB domain–mediated homophilic interactions may recruit membrane cholesterol into the vicinity of the complex, adding a sterol-rich microsurrounding to associated proteins without the need for preformed rafts from the membrane. In fact, podocin expression in cultured mammalian cells results in the increased formation of detergent-resistant cholesterol-rich membrane fractions (T.B., unpublished data).

PALMITOYLATION REGULATES INTERACTION WITH CHOLESTEROL

If we now understand that lipid–protein interactions are important for regulating ion channel activity and the function of the slit diaphragm protein supercomplex, then the immediate question that arises is whether cholesterol interaction with the complex is regulated dynamically. Indeed, this seems to be the case. Another level of complexity is added of course by the fact that cholesterol interaction is regulated through palmitoylation of podocin and MEC-2. Palmitoylation is a reversible posttranslational modification of proteins and refers to the addition of palmitate (a 16-carbon fatty acid) to the side chain of an internal cysteine residue (Figure 3). In the case of the most common S-palmitoylation, palmitate is attached to the protein through a reversible thioesther linkage.34 Many palmitoylated proteins undergo cycles of palmitoylation and depalmitoylation, which are tightly regulated: Palmitoylation is catalyzed by protein acyltransferases, and depalmitoylation requires acylprotein thioesterases.35 The functional consequences of palmitoylation are diverse. Palmitoylation facilitates the association of proteins with membranes, regulates protein stability, and more recently identifies a targeting motif.36,37

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

(A) Palmitoylation, the addition of a 16-carbon fatty acid to the side chain of a cysteine residue, is a reversible posttranslational modification. (B) Cholesterol interaction of podocin and MEC-2 requires palmitoylation of the PHB domain (blue) and a hydrophobic region (yellow) adjacent to the PHB domain.

Podocin and MEC-2 are palmitoylated at two conserved cysteine residues that regulate their interaction with cholesterol.23 Mutation of the two cysteine residues to alanine not only abrogates palmitoylation but also dramatically decreases the capacity of cholesterol binding without affecting targeting to the plasma membrane or the formation of high molecular weight supercomplexes.23 Thus, dynamic changes in the palmitoylation state of PHB proteins determine the amount of cholesterol recruited to the PHB-protein–based signaling complex. Palmitoylation was previously regarded as a posttranslational modification for targeting of proteins into preformed lipid rafts.38 That palmitoylation regulates lipid-binding properties of proteins adds a new twist to this model; multiprotein complexes based on PHB domain–mediated homophilic interactions dynamically recruit membrane cholesterol and other lipids into the vicinity of the complex to add a sterol-rich microsurrounding to associated proteins, a process that is regulated dynamically through palmitoylation.

Regulation of the lipid-binding properties of the podocin-based protein–lipid supercomplex may be even more complex. however. Podocin and MEC-2 are thought to decorate the inner leaflet of the plasma membrane with a hydrophobic region at the leaflet and amino and carboxy terminal tails facing the cytoplasm. Thus, palmitoylation regulates cholesterol interaction at the inner leaflet of the plasma membrane. The C. elegans MEC-2 mechanotransduction complex contains four other proteins, and the same may be true for podocin: The degenerin/epithelial Na+ channel proteins MEC-4 and MEC-10, which are thought to form the pore of the channel (TRPC6 ion channels in the case of podocin), the paraoxonase-like protein MEC-6, and UNC-24.28,30,39,40 UNC-24 and MEC-6 may also affect the binding or metabolism of lipids associated with the MEC-4/MEC-10 channel. UNC-24 is a PHB domain protein as well, but, unlike MEC-2, it has an additional domain (sterol carrier protein domain 2) that is similar to regions of nonspecific lipid transport proteins.41 Vertebrates have similar two-domain SLP-1 proteins. Nonspecific lipid transport proteins serve as intracellular carriers of cholesterol and other sterols, so the association of a similar domain with a cholesterol-binding PHB domain is suggestive that the two domains shuttle cholesterol and other sterols into the plasma membrane.40,42 In contrast to MEC-2 and UNC-24, MEC-6 has a single membrane-spanning domain that puts most of the protein on the extracellular side of the membrane.39 The similarity of MEC-6 with paraoxonases may indicate that it, too, affects the cholesterol content of the membrane, albeit at the outer leaflet of the bilayer, because two of the three vertebrate paraoxonases are secreted and associated with cholesterol-containing HDL particles. The third paraoxonase, PON-2, is, like MEC-6, a widely expressed membrane protein.43 It is also expressed in podocytes. We speculate that MEC-6 and, by analogy, PON-2 are involved in modifying or maintaining associated lipids on the external side of the lipid bilayer, but how these proteins contribute to the long-term marriage between podocin and cholesterol at the slit diaphragm of podocytes is unclear.

MECHANOSENSATION IN THE KIDNEY

Interaction with and recruitment of cholesterol into the slit diaphragm protein complex have been suggested for several years,18,27,32 but what is the critical physiologic function? Podocin is part of a multiprotein channel complex with the TRPC6 ion channel, the transmembrane proteins neph1 and nephrin, and a number of other proteins that provide the tight link to underlying cytoskeleton. The protein composition of the slit diaphragm protein complex has striking similarities to the MEC-2 touch receptor (Figure 2). Thus, it is tempting to speculate that podocin-associated ion channels serve a similar mechanosensory function25 (Figure 4). Indeed, the TRPC6 channel is mutated in genetic forms of proteinuric kidney disease6,8 and serves as a mechanosensory ion channel.44 Hypo-osmotic and pressure-induced stretch activates TRPC6 independent of second messenger signaling and likely occurs through direct sensing of membrane stretch. Experimentally, channel activation is blocked by the tarantula peptide GsMTx-4, a peptide known to inhibit specifically mechanosensitive ion channels by inserting in the outer membrane leaflet and modifying boundary lipids that are crucial for channel exposure and opening.44 Whether this toxin directly interferes with cholesterol binding to channel-associated proteins such as MEC-2 and podocin is unclear, but why is cholesterol required for stretch activation of these channels? Cholesterol, probably together with other lipids including glycosphingolipids, modulates structural and elastic properties of the bilayer; cholesterol decreases the area per phospholipid molecule and increases the thickness of the membrane bilayer.45 Furthermore, cholesterol recruited through podocin may decrease the elasticity of the plasma membrane, resulting in a more rigid membrane directly adjacent to the channel complex.46,47

Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

The similarity of the podocin-associated proteins to the well-defined MEC-2 touch channel complex suggests a similar role in mediating mechanosensation at the slit diaphragm of podocytes.

Taken together, it is tempting to conclude that the slit diaphragm–ion channel supercomplex is involved in mediating pressure sensation in podocytes. Podocyte secondary processes contain a highly regulated, actin-based cytoskeleton that consists of a cortical actin meshwork and highly ordered contractile central actin cables.48 Although still highly speculative, stretch-induced calcium influx at the mechanosensor of the slit diaphragm might regulate these contractile actin cables, leading to changes in foot process morphology and modulation of the filtration area and permeability of the kidney filter.

DISCLOSURES

None.

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (DFG BE2212 to T.B.) and the Center for Molecular Medicine (to T.B.).

We apologize to colleagues whose work was not cited because of length restrictions.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • ↵1 The 1957 movie of Cary Grant and Deborah Kerr.

  • Copyright © 2009 by the American Society of Nephrology

REFERENCES

  1. ↵
    Ly J, Alexander M, Quaggin SE: A podocentric view of nephrology. Curr Opin Nephrol Hypertens 13 : 299– 305, 2004
    OpenUrlCrossRefPubMed
  2. ↵
    Tryggvason K, Wartiovaara J: Molecular basis of glomerular permselectivity. Curr Opin Nephrol Hypertens 10 : 543– 549, 2001
    OpenUrlCrossRefPubMed
  3. ↵
    Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24 : 349– 354, 2000
    OpenUrlCrossRefPubMed
  4. Doublier S, Ruotsalainen V, Salvidio G, Lupia E, Biancone L, Conaldi PG, Reponen P, Tryggvason K, Camussi G: Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. Am J Pathol 158 : 1723– 1731, 2001
    OpenUrlCrossRefPubMed
  5. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell 1 : 575– 582, 1998
    OpenUrlCrossRefPubMed
  6. ↵
    Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR: TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37 : 739– 744, 2005
    OpenUrlCrossRefPubMed
  7. Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS: Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286 : 312– 315, 1999
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg, PB: A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308 : 1801– 1804, 2005
    OpenUrlAbstract/FREE Full Text
  9. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR: Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24 : 251– 256, 2000
    OpenUrlCrossRefPubMed
  10. ↵
    Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O'Toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F: Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38 : 1397– 1405, 2006
    OpenUrlCrossRefPubMed
  11. ↵
    Benzing T: Signaling at the slit diaphragm. J Am Soc Nephrol 15 : 1382– 1391, 2004
    OpenUrlFREE Full Text
  12. Huber TB, Benzing T: The slit diaphragm: A signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens 14 : 211– 216, 2005
    OpenUrlCrossRefPubMed
  13. Garg P, Verma R, Holzman LB: Slit diaphragm junctional complex and regulation of the cytoskeleton. Nephron Exp Nephrol 106 : e67– e72, 2007
    OpenUrlCrossRefPubMed
  14. ↵
    Johnstone DB, Holzman LB: Clinical impact of research on the podocyte slit diaphragm. Nat Clin Pract Nephrol 2 : 271– 282, 2006
    OpenUrlCrossRefPubMed
  15. ↵
    Huber TB, Hartleben B, Kim J, Schmidts M, Schermer B, Keil A, Egger L, Lecha RL, Borner C, Pavenstadt H, Shaw AS, Walz G, Benzing T: Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol 23 : 4917– 4928, 2003
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Huber TB, Kottgen M, Schilling B, Walz G, Benzing T: Interaction with podocin facilitates nephrin signaling. J Biol Chem 276 : 41543– 41546, 2001
    OpenUrlAbstract/FREE Full Text
  17. Huber TB, Schmidts M, Gerke P, Schermer B, Zahn A, Hartleben B, Sellin L, Walz G, Benzing T: The carboxyl terminus of Neph family members binds to the PDZ domain protein zonula occludens-1. J Biol Chem 278 : 13417– 13421, 2003
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Huber TB, Simons M, Hartleben B, Sernetz L, Schmidts M, Gundlach E, Saleem MA, Walz G, Benzing T: Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet 12 : 3397– 3405, 2003
    OpenUrlCrossRefPubMed
  19. Verma R, Wharram B, Kovari I, Kunkel R, Nihalani D, Wary KK, Wiggins RC, Killen P, Holzman LB: Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin. J Biol Chem 278 : 20716– 20723, 2003
    OpenUrlAbstract/FREE Full Text
  20. Blasutig IM, New LA, Thanabalasuriar A, Dayarathna TK, Goudreault M, Quaggin SE, Li SS, Gruenheid S, Jones N, Pawson T: Phosphorylated YDXV motifs and Nck SH2/SH3 adaptors act cooperatively to induce actin reorganization. Mol Cell Biol 28 : 2035– 2046, 2008
    OpenUrlAbstract/FREE Full Text
  21. Jones N, Blasutig IM, Eremina V, Ruston JM, Bladt F, Li H, Huang H, Larose L, Li SS, Takano T, Quaggin SE, Pawson T: Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 440 : 818– 823, 2006
    OpenUrlCrossRefPubMed
  22. ↵
    Verma R, Kovari I, Soofi A, Nihalani D, Patrie K, Holzman LB: Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest 116 : 1346– 1359, 2006
    OpenUrlCrossRefPubMed
  23. ↵
    Huber TB, Schermer B, Muller RU, Hohne M, Bartram M, Calixto A, Hagmann H, Reinhardt C, Koos F, Kunzelmann K, Shirokova E, Krautwurst D, Harteneck C, Simons M, Pavenstadt H, Kerjaschki D, Thiele C, Walz G, Chalfie M, Benzing T: Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci U S A 103 : 17079– 17086, 2006
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Morrow IC, Parton RG: Flotillins and the PHB domain protein family: rafts, worms and anaesthetics. Traffic 6 : 725– 740, 2005
    OpenUrlCrossRefPubMed
  25. ↵
    Huber TB, Schermer B, Benzing T: Podocin organizes ion channel-lipid supercomplexes: Implications for mechanosensation at the slit diaphragm. Nephron Exp Nephrol 106 : e27– e31, 2007
    OpenUrlCrossRefPubMed
  26. ↵
    Browman DT, Hoegg MB, Robbins SM: The SPFH domain-containing proteins: More than lipid raft markers. Trends Cell Biol 17 : 394– 402, 2007
    OpenUrlCrossRefPubMed
  27. ↵
    Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P: Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 108 : 1621– 1629, 2001
    OpenUrlCrossRefPubMed
  28. ↵
    Goodman MB, Ernstrom GG, Chelur DS, O'Hagan R, Yao CA, Chalfie M: MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation. Nature 415 : 1039– 1042, 2002
    OpenUrlCrossRefPubMed
  29. ↵
    Huang M, Gu G, Ferguson EL, Chalfie M: A stomatin-like protein necessary for mechanosensation in C. elegans. Nature 378 : 292– 295, 1995
    OpenUrlCrossRefPubMed
  30. ↵
    O'Hagan R, Chalfie M, Goodman MB: The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals. Nat Neurosci 8 : 43– 50, 2005
    OpenUrlCrossRefPubMed
  31. ↵
    Kurzchalia TV, Ward S: Why do worms need cholesterol? Nat Cell Biol 5 : 684– 688, 2003
    OpenUrlCrossRefPubMed
  32. ↵
    Simons K, Ikonen E: Functional rafts in cell membranes. Nature 387 : 569– 572, 1997
    OpenUrlCrossRefPubMed
  33. ↵
    Simons K, Toomre D: Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1 : 31– 39, 2000
    OpenUrlCrossRefPubMed
  34. ↵
    Nadolski MJ, Linder ME: Protein lipidation. FEBS J 274 : 5202– 5210, 2007
    OpenUrlCrossRefPubMed
  35. ↵
    Linder ME, Deschenes RJ: Palmitoylation: Policing protein stability and traffic. Nat Rev Mol Cell Biol 8 : 74– 84, 2007
    OpenUrlCrossRefPubMed
  36. ↵
    Neumann-Giesen C, Falkenbach B, Beicht P, Claasen S, Luers G, Stuermer CA, Herzog V, Tikkanen R: Membrane and raft association of reggie-1/flotillin-2: Role of myristoylation, palmitoylation and oligomerization and induction of filopodia by overexpression. Biochem J 378 : 509– 518, 2004
    OpenUrlCrossRefPubMed
  37. ↵
    Morrow IC, Rea S, Martin S, Prior IA, Prohaska R, Hancock JF, James DE, Parton RG: Flotillin-1/reggie-2 traffics to surface raft domains via a novel Golgi-independent pathway: Identification of a novel membrane targeting domain and a role for palmitoylation. J Biol Chem 277 : 48834– 48841, 2002
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Resh MD: Palmitoylation of ligands, receptors, and intracellular signaling molecules. Sci STKE 2006 : re14 , 2006
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Chelur DS, Ernstrom GG, Goodman MB, Yao CA, Chen L, O'Hagaan R, Chalfie M: The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel. Nature 420 : 669– 673, 2002
    OpenUrlCrossRefPubMed
  40. ↵
    Zhang S, Arnadottir J, Keller C, Caldwell GA, Yao CA, Chalfie M: MEC-2 is recruited to the putative mechanosensory complex in C. elegans touch receptor neurons through its stomatin-like domain. Curr Biol 14 : 1888– 1896, 2004
    OpenUrlCrossRefPubMed
  41. ↵
    Barnes TM, Jin Y, Horvitz HR, Ruvkun G, Hekimi S: The Caenorhabditis elegans behavioral gene unc-24 encodes a novel bipartite protein similar to both erythrocyte band 7.2 (stomatin) and nonspecific lipid transfer protein. J Neurochem 67 : 46– 57, 1996
    OpenUrlPubMed
  42. ↵
    Seidel G, Prohaska R: Molecular cloning of hSLP-1, a novel human brain-specific member of the band 7/MEC-2 family similar to Caenorhabditis elegans UNC-24. Gene 225 : 23– 29, 1998
    OpenUrlCrossRefPubMed
  43. ↵
    Getz GS, Reardon CA: Paraoxonase, a cardioprotective enzyme: Continuing issues. Curr Opin Lipidol 15 : 261– 267, 2004
    OpenUrlCrossRefPubMed
  44. ↵
    Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL: A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci U S A 103 : 16586– 16591, 2006
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Lecuyer H, Dervichian DG: Structure of aqueous mixtures of lecithin and cholesterol. J Mol Biol 45 : 39– 57, 1969
    OpenUrlCrossRefPubMed
  46. ↵
    Needham D, Nunn RS: Elastic deformation and failure of lipid bilayer membranes containing cholesterol. Biophys J 58 : 997– 1009, 1990
    OpenUrlCrossRefPubMed
  47. ↵
    Rawicz W, Smith BA, McIntosh TJ, Simon SA, Evans EA: Elasticity, strength, and water permeability of bilayers that contain raft microdomain-forming lipids. Biophys J 94 : 4725– 4736, 2008
    OpenUrlCrossRefPubMed
  48. ↵
    Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P: Actin up: Regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol 17 : 428– 437, 2007
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 20 (3)
Journal of the American Society of Nephrology
Vol. 20, Issue 3
March 2009
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Lipid–Protein Interactions along the Slit Diaphragm of Podocytes
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Lipid–Protein Interactions along the Slit Diaphragm of Podocytes
Bernhard Schermer, Thomas Benzing
JASN Mar 2009, 20 (3) 473-478; DOI: 10.1681/ASN.2008070694

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Lipid–Protein Interactions along the Slit Diaphragm of Podocytes
Bernhard Schermer, Thomas Benzing
JASN Mar 2009, 20 (3) 473-478; DOI: 10.1681/ASN.2008070694
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • PODOCIN AND CHOLESTEROL–AN AFFAIR TO REMEMBER1
    • PALMITOYLATION REGULATES INTERACTION WITH CHOLESTEROL
    • MECHANOSENSATION IN THE KIDNEY
    • DISCLOSURES
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

UP FRONT MATTERS

  • COVID-19 and APOL1: Understanding Disease Mechanisms through Clinical Observation
  • The Aftermath of AKI: Recurrent AKI, Acute Kidney Disease, and CKD Progression
  • Sphingosine-1-Phosphate Metabolism and Signaling in Kidney Diseases
Show more UP FRONT MATTERS

Brief Review

  • HIV-Positive Kidney Donor Selection for HIV-Positive Transplant Recipients
  • The Labile Side of Iron Supplementation in CKD
  • Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression
Show more Brief Review

Cited By...

  • Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization
  • Phosphoproteomic Analysis Reveals Regulatory Mechanisms at the Kidney Filtration Barrier
  • A Disease-causing Mutation Illuminates the Protein Membrane Topology of the Kidney-expressed Prohibitin Homology (PHB) Domain Protein Podocin
  • Stiffened lipid platforms at molecular force foci
  • Life Without Nephrin: It's for the Birds
  • Lipotoxicity in Diabetic Nephropathy: The Potential Role of Fatty Acid Oxidation
  • The Promise of Well-Being: Stay in Shape with N(i)ck
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire