SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance.
Actomyosin
/ metabolism
Animals
Cell Surface Extensions
/ metabolism
Cells, Cultured
Disease Models, Animal
Female
GTPase-Activating Proteins
/ deficiency
Glomerulosclerosis, Focal Segmental
/ etiology
Humans
Integrins
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Nephrotic Syndrome
/ etiology
Podocytes
/ metabolism
Protein Interaction Mapping
Proteome
Pseudopodia
/ metabolism
Transcriptome
rho GTP-Binding Proteins
/ metabolism
Rho GTPase
RhoGAP
Srgap1
cell adhesion
cell signaling
focal segmental glomerulosclerosis
glomerular epithelial cells
nephrotic syndrome
podocyte
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
05
08
2020
accepted:
15
11
2020
pubmed:
31
1
2021
medline:
22
9
2021
entrez:
30
1
2021
Statut:
ppublish
Résumé
Previous research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking. We conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped We demonstrated SRGAP1 localization to podocyte foot processes SRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.
Sections du résumé
BACKGROUND
Previous research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking.
METHODS
We conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped
RESULTS
We demonstrated SRGAP1 localization to podocyte foot processes
CONCLUSIONS
SRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.
Identifiants
pubmed: 33514561
pii: 00001751-202103000-00010
doi: 10.1681/ASN.2020081126
pmc: PMC7920176
doi:
Substances chimiques
GTPase-Activating Proteins
0
Integrins
0
Proteome
0
SRGAP1 protein, human
0
Actomyosin
9013-26-7
rho GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
563-579Informations de copyright
Copyright © 2021 by the American Society of Nephrology.
Références
Grahammer F, Schell C, Huber TB: The podocyte slit diaphragm--from a thin grey line to a complex signalling hub. Nat Rev Nephrol 9: 587–598, 2013 23999399
Perico L, Conti S, Benigni A, Remuzzi G: Podocyte-actin dynamics in health and disease. Nat Rev Nephrol 12: 692–710, 2016 27573725
Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF: Minimal change disease and idiopathic FSGS: Manifestations of the same disease. Nat Rev Nephrol 12: 768–776, 2016 27748392
Kriz W, Shirato I, Nagata M, LeHir M, Lemley KV: The podocyte’s response to stress: The enigma of foot process effacement. Am J Physiol Renal Physiol 304: F333–F347, 2013 23235479
Butt L, Unnersjö-Jess D, Höhne M, Edwards A, Binz-Lotter J, Reilly D, et al.: A molecular mechanism explaining albuminuria in kidney disease. Nat Metab 2: 461–474, 2020 32694662
Schell C, Huber TB: The evolving complexity of the podocyte cytoskeleton. J Am Soc Nephrol 28: 3166–3174, 2017 28864466
Yu H, Suleiman H, Kim AH, Miner JH, Dani A, Shaw AS, et al.: Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol Cell Biol 33: 4755–4764, 2013 24061480
Robins R, Baldwin C, Aoudjit L, Côté JF, Gupta IR, Takano T: Rac1 activation in podocytes induces the spectrum of nephrotic syndrome. Kidney Int 92: 349–364, 2017 28483380
Blattner SM, Hodgin JB, Nishio M, Wylie SA, Saha J, Soofi AA, et al.: Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int 84: 920–930, 2013 23677246
Scott RP, Hawley SP, Ruston J, Du J, Brakebusch C, Jones N, et al.: Podocyte-specific loss of Cdc42 leads to congenital nephropathy. J Am Soc Nephrol 23: 1149–1154, 2012 22518006
Zhu L, Jiang R, Aoudjit L, Jones N, Takano T: Activation of RhoA in podocytes induces focal segmental glomerulosclerosis. J Am Soc Nephrol 22: 1621–1630, 2011 21804090
Wang L, Ellis MJ, Gomez JA, Eisner W, Fennell W, Howell DN, et al.: Mechanisms of the proteinuria induced by Rho GTPases. Kidney Int 81: 1075–1085, 2012 22278020
Etienne-Manneville S, Hall A: Rho GTPases in cell biology. Nature 420: 629–635, 2002 12478284
Aspenström P: Fast-cycling Rho GTPases. Small GTPases 11: 248–255, 2020 29157138
Müller PM, Rademacher J, Bagshaw RD, Wortmann C, Barth C, van Unen J, et al.: Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nat Cell Biol 22: 498–511, 2020 32203420
Matsuda J, Maier M, Aoudjit L, Baldwin C, Takano T: ARHGEF7 ( β -PIX) is required for the maintenance of podocyte architecture and glomerular function. J Am Soc Nephrol 31: 996–1008, 2020 32188698
Bagci H, Sriskandarajah N, Robert A, Boulais J, Elkholi IE, Tran V, et al.: Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nat Cell Biol 22: 120–134, 2020 31871319
Gillingham AK, Bertram J, Begum F, Munro S: In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation. eLife 8: e45916, 2019 31294692
Paul F, Zauber H, von Berg L, Rocks O, Daumke O, Selbach M: Quantitative GTPase affinity purification identifies rho family protein interaction partners. Mol Cell Proteomics 16: 73–85, 2017 27852748
Park JS, Ma W, O’Brien LL, Chung E, Guo JJ, Cheng JG, et al.: Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Dev Cell 23: 637–651, 2012 22902740
Kobayashi A, Valerius MT, Mugford JW, Carroll TJ, Self M, Oliver G, et al.: Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3: 169–181, 2008 18682239
Moeller MJ, Sanden SK, Soofi A, Wiggins RC, Holzman LB: Two gene fragments that direct podocyte-specific expression in transgenic mice. J Am Soc Nephrol 13: 1561–1567, 2002 12039985
Lee VW, Harris DC: Adriamycin nephropathy: A model of focal segmental glomerulosclerosis. Nephrology (Carlton) 16: 30–38, 2011 21175974
Rogg M, Yasuda-Yamahara M, Abed A, Dinse P, Helmstädter M, Conzelmann AC, et al.: The WD40-domain containing protein CORO2B is specifically enriched in glomerular podocytes and regulates the ventral actin cytoskeleton. Sci Rep 7: 15910, 2017 29162887
Schell C, Sabass B, Helmstaedter M, Geist F, Abed A, Yasuda-Yamahara M, et al. ARP3 controls the podocyte architecture at the kidney filtration barrier. Dev cell 47: 741–757.e8, 2018
Siegerist F, Ribback S, Dombrowski F, Amann K, Zimmermann U, Endlich K, et al.: Structured illumination microscopy and automatized image processing as a rapid diagnostic tool for podocyte effacement. Sci Rep 7: 11473, 2017 28904359
el Nahas AM, Bassett AH, Cope GH, Le Carpentier JE: Role of growth hormone in the development of experimental renal scarring. Kidney Int 40: 29–34, 1991 1921152
Schell C, Rogg M, Suhm M, Helmstädter M, Sellung D, Yasuda-Yamahara M, et al.: The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier. Proc Natl Acad Sci U S A 114: E4621–E4630, 2017 28536193
Saleem MA, O’Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, et al.: A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol 13: 630–638, 2002 11856766
Labun K, Montague TG, Krause M, Torres Cleuren YN, Tjeldnes H, Valen E: CHOPCHOP v3: Expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res 47: W171–W174, 2019 31106371
Sanjana NE, Shalem O, Zhang F: Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 11: 783–784, 2014 25075903
Coutinho-Budd J, Ghukasyan V, Zylka MJ, Polleux F: The F-BAR domains from srGAP1, srGAP2 and srGAP3 regulate membrane deformation differently. J Cell Sci 125: 3390–3401, 2012 22467852
Yasuda-Yamahara M, Rogg M, Yamahara K, Maier JI, Huber TB, Schell C: AIF1L regulates actomyosin contractility and filopodial extensions in human podocytes. PLoS One 13: e0200487, 2018 30001384
Knopf JD, Tholen S, Koczorowska MM, De Wever O, Biniossek ML, Schilling O: The stromal cell-surface protease fibroblast activation protein-α localizes to lipid rafts and is recruited to invadopodia. Biochim Biophys Acta 1853: 2515–2525, 2015 26209915
Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57, 2009 19131956
Mahi NA, Najafabadi MF, Pilarczyk M, Kouril M, Medvedovic M: GREIN: An interactive web platform for re-analyzing GEO RNA-seq data. Sci Rep 9: 7580, 2019 31110304
Afgan E, Baker D, van den Beek M, Blankenberg D, Bouvier D, Čech M, et al.: The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res 44: W3–W10, 2016 27137889
Chen S, Zhou Y, Chen Y, Gu J: fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34: i884–i890, 2018 30423086
Kim D, Langmead B, Salzberg SL: HISAT: A fast spliced aligner with low memory requirements. Nat Methods 12: 357–360, 2015 25751142
Liao Y, Smyth GK, Shi W: featureCounts: An efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30: 923–930, 2014 24227677
Love MI, Huber W, Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15: 550, 2014 25516281
Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE; Mouse Genome Database Group: Mouse Genome Database (MGD) 2019. Nucleic Acids Res 47: D801–D806, 2019 30407599
UniProt Consortium: UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res 47: D506–D515, 2019 30395287
Heasman SJ, Ridley AJ: Mammalian Rho GTPases: New insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9: 690–701, 2008 18719708
Mitchell AL, Attwood TK, Babbitt PC, Blum M, Bork P, Bridge A, et al.: InterPro in 2019: Improving coverage, classification and access to protein sequence annotations. Nucleic Acids Res 47: D351–D360, 2019 30398656
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al.: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 13: 2498–2504, 2003 14597658
Brunskill EW, Park JS, Chung E, Chen F, Magella B, Potter SS: Single cell dissection of early kidney development: Multilineage priming. Development 141: 3093–3101, 2014 25053437
Kann M, Ettou S, Jung YL, Lenz MO, Taglienti ME, Park PJ, et al.: Genome-wide analysis of Wilms’ tumor 1-controlled gene expression in podocytes reveals key regulatory mechanisms. J Am Soc Nephrol 26: 2097–2104, 2015 25636411
Rinschen MM, Gödel M, Grahammer F, Zschiedrich S, Helmstädter M, Kretz O, et al.: A multi-layered quantitative in vivo expression atlas of the podocyte unravels kidney disease candidate genes. Cell Rep 23: 2495–2508, 2018 29791858
Akilesh S, Suleiman H, Yu H, Stander MC, Lavin P, Gbadegesin R, et al.: Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest 121: 4127–4137, 2011 21911940
Itoh T, Erdmann KS, Roux A, Habermann B, Werner H, De Camilli P: Dynamin and the actin cytoskeleton cooperatively regulate plasma membrane invagination by BAR and F-BAR proteins. Dev Cell 9: 791–804, 2005 16326391
Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR: Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol 10: 778–790, 2009 19851336
Wiggan O, Shaw AE, DeLuca JG, Bamburg JR: ADF/cofilin regulates actomyosin assembly through competitive inhibition of myosin II binding to F-actin. Dev Cell 22: 530–543, 2012 22421043
Delorme V, Machacek M, DerMardirossian C, Anderson KL, Wittmann T, Hanein D, et al.: Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks. Dev Cell 13: 646–662, 2007 17981134
Guilluy C, Garcia-Mata R, Burridge K: Rho protein crosstalk: Another social network? Trends Cell Biol 21: 718–726, 2011 21924908
Martin K, Reimann A, Fritz RD, Ryu H, Jeon NL, Pertz O: Spatio-temporal co-ordination of RhoA, Rac1 and Cdc42 activation during prototypical edge protrusion and retraction dynamics. Sci Rep 6: 21901, 2016 26912264
Schell C, Baumhakl L, Salou S, Conzelmann AC, Meyer C, Helmstädter M, et al.: N-wasp is required for stabilization of podocyte foot processes. J Am Soc Nephrol 24: 713–721, 2013 23471198
Schell C, Wanner N, Huber TB: Glomerular development--shaping the multi-cellular filtration unit. Semin Cell Dev Biol 36: 39–49, 2014 25153928
Wong K, Ren XR, Huang YZ, Xie Y, Liu G, Saito H, et al.: Signal transduction in neuronal migration: Roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway. Cell 107: 209–221, 2001 11672528
Yamazaki D, Itoh T, Miki H, Takenawa T: srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity. Mol Biol Cell 24: 3393–3405, 2013 24006490
Liang X, Budnar S, Gupta S, Verma S, Han SP, Hill MM, et al.: Tyrosine dephosphorylated cortactin downregulates contractility at the epithelial zonula adherens through SRGAP1. Nat Commun 8: 790, 2017 28983097
Huang T, Zhou Y, Zhang J, Wong CC, Li W, Kwan JSH, et al.: SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis. Oncogene 37: 1159–1174, 2018 29234151
Kutys ML, Yamada KM: An extracellular-matrix-specific GEF-GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration. Nat Cell Biol 16: 909–917, 2014 25150978
Hwang DY, Kohl S, Fan X, Vivante A, Chan S, Dworschak GC, et al.: Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Hum Genet 134: 905–916, 2015 26026792
Fan X, Yang H, Kumar S, Tumelty KE, Pisarek-Horowitz A, Rasouly HM, et al.: SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion. JCI Insight 1: e86934, 2016 27882344
Combes AN, Wilson S, Phipson B, Binnie BB, Ju A, Lawlor KT, et al.: Haploinsufficiency for the Six2 gene increases nephron progenitor proliferation promoting branching and nephron number. Kidney Int 93: 589–598, 2018 29217079
Guan J, Wang D, Cao W, Zhao Y, Du R, Yuan H, et al.: SIX2 haploinsufficiency causes conductive hearing loss with ptosis in humans. J Hum Genet 61: 917–922, 2016 27383657
Shirato I: Podocyte process effacement in vivo . Microsc Res Tech 57: 241–246, 200212012392
Suleiman HY, Roth R, Jain S, Heuser JE, Shaw AS, Miner JH: Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopy. JCI Insight 2: e94137, 2017 28814668
Vega FM, Fruhwirth G, Ng T, Ridley AJ: RhoA and RhoC have distinct roles in migration and invasion by acting through different targets. J Cell Biol 193: 655–665, 2011 21576392