Human erythrocytes: cytoskeleton and its origin

  • Ayelén D. Nigra
  • Cesar H. Casale
  • Verónica S. SantanderEmail author


In the last few years, erythrocytes have emerged as the main determinant of blood rheology. In mammals, these cells are devoid of nuclei and are, therefore, unable to divide. Consequently, all circulating erythrocytes come from erythropoiesis, a process in the bone marrow in which several modifications are induced in the expression of membrane and cytoskeletal proteins, and different vertical and horizontal interactions are established between them. Cytoskeleton components play an important role in this process, which explains why they and the interaction between them have been the focus of much recent research. Moreover, in mature erythrocytes, the cytoskeleton integrity is also essential, because the cytoskeleton confers remarkable deformability and stability on the erythrocytes, thus enabling them to undergo deformation in microcirculation. Defects in the cytoskeleton produce changes in erythrocyte deformability and stability, affecting cell viability and rheological properties. Such abnormalities are seen in different pathologies of special interest, such as different types of anemia, hypertension, and diabetes, among others. This review highlights the main findings in mammalian erythrocytes and their progenitors regarding the presence, conformation and function of the three main components of the cytoskeleton: actin, intermediate filaments, and tubulin.


Erythrocytes Erythropoiesis Cytoskeleton Tubulin Actin Intermediate filaments 



This study was supported by grants from Agencia Nacional de Promoción Científica y Tecnología (# 141/13), Consejo Nacional de Investigaciones Científicas y Técnicas, and Secretaría de Ciencia y Técnica de la Universidad Nacional de Río Cuarto. This review is dedicated to the memory of Marina Rafaela Amaiden, who will remain forever in our hearts.


  1. 1.
    Ferru E, Giger K, Pantaleo A, Campanella E, Grey J, Ritchie K, Vono R, Turrini F, Low PS (2011) Regulation of membrane-cytoskeletal interactions by tyrosine phosphorylation of erythrocyte band 3. Blood 117:5998–6006PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Lanotte L, Mauer J, Mendez S, Fedosov DA, Fromental JM, Claveria V, Nicoud F, Gompper G, Abkarian M (2016) Red cells’ dynamic morphologies govern blood shear thinning under microcirculatory flow conditions. Proc Natl Acad Sci USA 113:13289–13294PubMedCrossRefGoogle Scholar
  3. 3.
    Papayannopoulou Th, Abkowitz J, D’Andrea A, Migliaccio AR (2009) Biology of erythtropoiesis, erythroid differentiation and maturation. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Silberstein LE, McGlave P, Heslop (eds) Hematology: basic principles and practice, 5th edn. Elsevier, Philadelphia, pp 276–294Google Scholar
  4. 4.
    Migliaccio AR (2010) Erythroblast enucleation. Haematologica 95:1985–1988PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pasini EM, Kirkegaard M, Mortensen P, Lutz HU, Thomas AW, Mann M (2006) In-depth analysis of the membrane and cytosolic proteome of red blood cells. Blood 108:791–801PubMedCrossRefGoogle Scholar
  6. 6.
    Orkin SH (2000) Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet 1:57–64PubMedCrossRefGoogle Scholar
  7. 7.
    Bauer A, Gandrillon O, Samarut J, Beug H (2001) Nuclear receptors in hematopoietic development: cooperation with growth factor receptors in regulation of proliferation and differentiation. In: Zon L (ed) Hematopoiesis: a developmental approach. Oxford University Press, Oxford, pp 268–290Google Scholar
  8. 8.
    Sohawon D, Lau KK, Lau T, Bowden DK (2012) Extra-medullary haematopoiesis: a pictorial review of its typical and atypical locations. J Med Imaging Radiat Oncol 56:538–544PubMedCrossRefGoogle Scholar
  9. 9.
    Orphanidou-Vlachou E, Tziakouri-Shiakalli C, Georgiades CS (2014) Extramedullary hemopoiesis. Semin Ultrasound CT MR 35:255–262PubMedCrossRefGoogle Scholar
  10. 10.
    Kiel MJ, Iwashita T, Yilmaz OH, Morrison SJ (2005) Spatial differences in hematopoiesis but not in stem cells indicate a lack of regional patterning in definitive hematopoietic stem cells. Dev Biol 283:29–39PubMedCrossRefGoogle Scholar
  11. 11.
    Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132:631–644PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Rhodes MM, Kopsombut P, Bondurant MC, Price JO, Koury MJ (2008) Adherence to macrophages in erythroblastic islands enhances erythroblast proliferation and increases erythrocyte production by a different mechanism than erythropoietin. Blood 111:1700–1708PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Fischer S, Kurbatova P, Bessonov N, Gandrillon O, Volpert V, Crauste F (2012) Modeling erythroblastic islands: using a hybrid model to assess the function of central macrophage. J Theor Biol 298:92–106PubMedCrossRefGoogle Scholar
  14. 14.
    Eymard N, Bessonov N, Gandrillon O, Koury MJ, Volpert V (2012) The role of spatial organization of cells in erythropoiesis. J Math Biol 70:71–97CrossRefGoogle Scholar
  15. 15.
    Leimberg JM, Prus E, Link G, Fibach E, Konijn AM (2008) Iron-chelator complexes as iron sources for early developing human erythroid precursors. Transl Res 151:88–96PubMedCrossRefGoogle Scholar
  16. 16.
    Giger KM, Kalfa TA (2015) Phylogenetic and ontogenetic view of erythroblastic islands. Biomed Res Int 2015:873628PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Migliaccio AR, Masselli E, Varricchio L, Whitsett C (2012) Ex-vivo expansion of red blood cells: how real for transfusion in humans? Blood Rev 26:81–95PubMedCrossRefGoogle Scholar
  18. 18.
    Wu H, Liu X, Jaenisch R, Lodish HF (1995) Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83:59–67PubMedCrossRefGoogle Scholar
  19. 19.
    Peslak SA, Wenger J, Bemis JC, Kingsley PD, Koniski AD, McGrath KE, Palis J (2012) EPO-mediated expansion of late-stage erythroid progenitors in the bone marrow initiates recovery from sublethal radiation stress. Blood 120:2501–2511PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Palis J (2014) Primitive and definitive erythropoiesis in mammals. Front Physiol 5:3PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Koury MJ, Bondurant MC (1988) Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells. J Cell Physiol 137:65–74PubMedCrossRefGoogle Scholar
  22. 22.
    Sawada K, Krantz SB, Dessypris EN, Koury ST, Sawyer ST (1989) Human colony-forming units-erythroid do not require accessory cells, but do require direct interaction with insulin-like growth factor I and/or insulin for erythroid development. J Clin Invest 83:1701–1709PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Chasis JA (2011) Marching single file or 2 abreast. Blood 118:6–7PubMedCrossRefGoogle Scholar
  24. 24.
    Pronk CJ, Bryder D (2011) Flow cytometry-based identification of immature myeloerythroid development. Methods Mol Biol 699:275–293PubMedCrossRefGoogle Scholar
  25. 25.
    Pronk CJ, Rossi DJ, Månsson R, Attema JL, Norddahl GL, Chan CK, Sigvardsson M, Weissman IL, Bryder D (2007) Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1:428–442PubMedCrossRefGoogle Scholar
  26. 26.
    Harandi OF, Hedge S, Wu DC, McKeone D, Paulson RF (2010) Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors. J Clin Invest 120:4507–4519PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Xiang J, Wu DC, Chen Y, Paulson RF (2015) In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors. Blood 125:1803–1812PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Bennett LF, Liao C, Paulson RF (2018) Stress erythropoiesis model systems. Methods Mol Biol 1698:91–102PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Wickrema A, Koury ST, Dai CH, Krantz SB (1994) Changes in cytoskeletal proteins and their mRNAs during maturation of human erythroid progenitor cells. J Cell Physiol 160:417–426PubMedCrossRefGoogle Scholar
  30. 30.
    Wang L, Yang L, Filippi MD, Williams DA, Zheng Y (2006) Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood 107:98–105PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Watanabe S, De Zan T, Ishizaki T, Yasuda S, Kamijo H, Yamada D, Aoki T, Kiyonari H, Kaneko H, Shimizu R, Yamamoto M, Goshima G, Narumiya S (2013) Loss of a Rho-regulated actin nucleator, mDia2, impairs cytokinesis during mouse fetal erythropoiesis. Cell Rep 5:926–932PubMedCrossRefGoogle Scholar
  32. 32.
    Plett PA, Abonour R, Frankovitz SM, Orschell CM (2004) Impact of modeled microgravity on migration, differentiation, and cell cycle control of primitive human hematopoietic progenitor cells. Exp Hematol 32:773–781PubMedCrossRefGoogle Scholar
  33. 33.
    Bruns I, Cadeddu RP, Brueckmann I, Frobel J, Geyh S, Bust S, Fischer JC, Roels F, Wilk CM, Schildberg FA, Hunerliturkoglu AN, Zilkens C, Jager M, Steidl U, Zohren F, Fenk R, Kobbe G, Brors B, Czibere A, Schroeder T, Trumpp A, Haas R (2012) Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. Blood 120:2620–2630PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Nigra A, Santander V, Dircio-Maldonado R, Amaiden MR, Monesterolo N, Flores-Guzman P, Muhlberger T, Rivelli J, Campetelli A, Mayani H, Casale C (2017) Tubulin is retained throughout the human hematopoietic/erythroid cell differentiation process and plays a structural role in sedimentable fraction of mature erythrocytes. Int J Biochem Cell Biol 91:29–36PubMedCrossRefGoogle Scholar
  35. 35.
    Wickrema A, Krantz SB, Winkelmann JC, Bondurant MC (1992) Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood 80:1940–1949PubMedCrossRefGoogle Scholar
  36. 36.
    Keerthivasan G, Wickrema A, Crispino JD (2011) Erythroblast enucleation. Stem Cells Int 2011:139851PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Chasis JA, Mohandas N (2008) Erythroblastic islands: niches for erythropoiesis. Blood 112:470–478PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Whyatt D, Lindeboom F, Karis A, Ferreira R, Milot E, Hendriks R, de Bruijn M, Langeveld A, Gribnau J, Grosveld F, Philipsen S (2000) An intrinsic but cell-nonautonomous defect in GATA-1-overexpressing mouse erythroid cells. Nature 406:519–524PubMedCrossRefGoogle Scholar
  39. 39.
    Chasis JA (2010) Red or green? Enucleation traffic light. Blood 116:3122PubMedCrossRefGoogle Scholar
  40. 40.
    Anselmo A, Lauranzano E, Soldani C, Ploia C, Angioni R, D’Amico G, Sarukhan A, Mazzon C, Viola A (2016) Identification of a novel agrin-dependent pathway in cell signaling and adhesion within the erythroid niche. Cell Death Differ 23:1322–1330PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chen K, Liu J, Heck S, Chasis JA, An X, Mohandas N (2009) Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci USA 106:17413–17418PubMedCrossRefGoogle Scholar
  42. 42.
    Rieu S, Geminard C, Rabesandratana H, Sainte-Marie J, Vidal M (2000) Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1. Eur J Biochem 267:583–590PubMedCrossRefGoogle Scholar
  43. 43.
    Grosso R, Fader CM, Colombo MI (2017) Autophagy: a necessary event during erythropoiesis. Blood Rev 31:300–305PubMedCrossRefGoogle Scholar
  44. 44.
    Uras IZ, Scheicher RM, Kollmann K, Glösmann M, Prchal-Murphy M, Tigan AS, Fux DA, Altamura S, Neves J, Muckenthaler MU, Bennett KL, Kubicek S, Hinds PW, von Lindern M, Sexl V (2017) Cdk6 contributes to cytoskeletal stability in erythroid cells. Haematologica 102:995–1005PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA (2012) Signaling and cytoskeletal requirements in erythroblast enucleation. Blood 119:6118–6127PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Yoshida H, Kawane K, Koike M, Mori Y, Uchiyama Y, Nagata S (2005) Phosphatidylserine-dependent engulfment by macrophages of nuclei fromerythroid precursor cells. Nature 437:754–758PubMedCrossRefGoogle Scholar
  47. 47.
    Simpson CF, Kling JM (1967) The mechanism of denucleation in circulating erythroblasts. J Cell Biol 35:237–245PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Koury ST, Koury MJ, Bondurant MC (1989) Cytoskeletal distribution and function during the maturation and enucleation of mammalian erythroblasts. J Cell Biol 109:3005–3013PubMedCrossRefGoogle Scholar
  49. 49.
    Chasis JA, Prenant M, Leung A, Mohandas N (1989) Membrane assembly and remodeling during reticulocyte maturation. Blood 74:1112–1120PubMedCrossRefGoogle Scholar
  50. 50.
    Keerthivasan G, Small S, Liu H, Wickrema A, Crispino JD (2010) Vesicle trafficking plays a novel role in erythroblast enucleation. Blood 116:3331–3340PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Wang J, Ramirez T, Ji P, Jayapal SR, Lodish HF, Murata-Hori M (2012) Mammalian erythroblast enucleation requires PI3K-dependent cell polarization. J Cell Sci 125:340–349PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kobayashi I, Ubukawa K, Sugawara K, Asanuma K, Guo YM, Yamashita J, Takahashi N, Sawada K, Nunomura W (2016) Erythroblast enucleation is a dynein-dependent process. Exp Hematol 44:247–256PubMedCrossRefGoogle Scholar
  53. 53.
    Thom CS, Traxler EA, Khandros E, Nickas JM, Zhou OY, Lazarus JE, Silva AP, Prabhu D, Yao Y, Aribeana C, Fuchs SY, Mackay JP, Holzbaur EL, Weiss MJ (2014) Trim58 degrades Dynein and regulates terminal erythropoiesis. Dev Cell 30:688–700PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Ji P (2015) New insights into the mechanisms of mammalian erythroid chromatin condensation and enucleation. Int Rev Cell Mol Biol 316:159–182PubMedCrossRefGoogle Scholar
  55. 55.
    Sangiorgi F, Woods CM, Lazarides E (1990) Vimentin downregulation is an inherent feature of murine erythropoiesis and occurs independently of lineage. Development 110:85–96PubMedGoogle Scholar
  56. 56.
    Liu J, Guo X, Mohandas N, Chasis JA, An X (2010) Membrane remodeling during reticulocyte maturation. Blood 115:2021–2027PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kalfa TA, Zheng Y (2014) Rho GTPases in erythroid maturation. Curr Opin Hematol 21:165–171PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ubukawa K, Guo YM, Takahashi M, Hirokawa M, Michishita Y, Nara M, Tagawa H, Takahashi N, Komatsuda A, Nunomura W, Takakuwa Y, Sawada K (2012) Enucleation of human erythroblasts involves non-muscle myosin IIB. Blood 119:1036–1044PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Araki K, Sugawara K, Hayakawa EH, Ubukawa K, Kobayashi I, Wakui H, Takahashi N, Sawada K, Mochizuki H, Nunomura W (2018) The localization of alpha-synuclein in the process of differentiation of human erythroid cells. Int J Hematol 108:130–138PubMedCrossRefGoogle Scholar
  60. 60.
    McGrath KE, Bushnell TP, Palis J (2008) Multispectral imaging of hematopoietic cells: where flow meets morphology. J Immunol Methods 336:91–97PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lee JC, Gimm JA, Lo AJ, Koury MJ, Krauss SW, Mohandas N, Chasis JA (2004) Mechanism of protein sorting during erythroblast enucleation: role of cytoskeletal connectivity. Blood 103:1912–1919PubMedCrossRefGoogle Scholar
  62. 62.
    Skutelsky E, Farquhar MG (1976) Variations in distribution of con A receptor sites and anionic groups during red blood cell differentiation in the rat. J Cell Biol 71:218–231PubMedCrossRefGoogle Scholar
  63. 63.
    Lew VL, Raftos JE, Sorette M, Bookchin RM, Mohandas N (1995) Generation of normal human red cell volume, hemoglobin content, and membrane area distributions by “birth” or regulation? Blood 86:334–341PubMedCrossRefGoogle Scholar
  64. 64.
    Malleret B, Xu F, Mohandas N, Suwanarusk R, Chu C, Leite JA, Low K, Turner C, Sriprawat K, Zhang R, Bertrand O, Colin Y, Costa FT, Ong CN, Ng ML, Lim CT, Nosten F, Renia L, Russell B (2013) Significant biochemical, biophysical and metabolic diversity in circulating human cord blood reticulocytes. PLoS One 8:e76062PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Li H, Yang J, Chu TT, Naidu R, Lu L, Chandramohanadas R, Dao M, Karniadakis GE (2018) Cytoskeleton remodeling induces membrane stiffness and stability changes of maturing reticulocytes. Biophys J 114:2014–2023PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Waugh RE, McKenney JB, Bauserman RG, Brooks DM, Valeri CR, Snyder LM (1997) Surface area and volume changes during maturation of reticulocytes in the circulation of the baboon. J Lab Clin Med 129:527–535PubMedCrossRefGoogle Scholar
  67. 67.
    Da Costa L, Mohandas N, Cynober T (2001) Temporal differences in membrane loss lead to distinct reticulocyte features in hereditary spherocytosis and in immune hemolytic anemia. Blood 98:2894–2899PubMedCrossRefGoogle Scholar
  68. 68.
    Mohandas N, An X (2012) Malaria and human red blood cells. Med Microbiol Immunol 201:593–598PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Chasis JA, Mohandas N (1986) Erythrocyte membrane deformability and stability: two distinct membrane properties that are independently regulated by skeletal protein associations. J Cell Biol 103:343–350PubMedCrossRefGoogle Scholar
  70. 70.
    Chasis JA, Coulombel L, Conboy J, McGee S, Andrews K, Kan YW, Mohandas N (1993) Differentiation-associated switches in protein 4.1 expression. Synthesis of multiple structural isoforms during normal human erythropoiesis. J Clin Invest 91:329–338PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Waugh RE, Huang YS, Arif BJ, Bauserman R, Palis J (2013) Development of membrane mechanical function during terminal stages of primitive erythropoiesis in mice. Exp Hematol 41:398–408PubMedCrossRefGoogle Scholar
  72. 72.
    Chu TTT, Sinha A, Malleret B, Suwanarusk R, Park JE, Naidu R, Das R, Dutta B, Ong ST, Verma NK, Chan JK, Nosten F, Rénia L, Sze SK, Russell B, Chandramohanadas R (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol 180:118–133PubMedCrossRefGoogle Scholar
  73. 73.
    Boal D (2012) Mechanics of the cell. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  74. 74.
    An X, Mohandas N (2008) Disorders of red cell membrane. Br J Haematol 141:367–375PubMedGoogle Scholar
  75. 75.
    Lazzareschi I, Curatola A, Pedicelli C, Castiglia D, Buonsenso D, Gatto A, Attinà G, Valentini P (2019) A previously unrecognized Ankyrin-1 mutation associated with Hereditary Spherocytosis in an Italian family. Eur J Haematol 10:1111Google Scholar
  76. 76.
    Xi Y, Wang L, Zhang P, Jia M, Li Z (2019) A novel mutation in SPTA1 identified by whole exome sequencing in a Chinese family for hereditary elliptocytosis presenting with hyperbilirubinemia: a case report. Medicine (Baltimore) 98:e15800CrossRefGoogle Scholar
  77. 77.
    Reithmeier RA, Casey JR, Kalli AC, Sansom MS, Alguel Y, Iwata S (2016) Band 3, the human red cell chloride/bicarbonate anion exchanger (AE1, SLC4A1), in a structural context. Biochim Biophys Acta 1858:1507–1532PubMedCrossRefGoogle Scholar
  78. 78.
    Danielczok JG, Terriac E, Hertz L, Petkova-Kirova P, Lautenschläger F, Laschke MW, Kaestner L (2017) Red blood cell passage of small capillaries is associated with transient Ca2+-mediated adaptations. Front Physiol 8:979PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Mohandas N, Gallagher PG (2008) Red cell membrane: past, present, and future. Blood 112:3939–3948PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Amaiden M, Monesterolo N, Santander V, Campetelli A, Arce C, Pie J, Hope S, Vatta M, Casale C (2012) Involvement of membrane tubulin in erythrocyte deformability and blood pressure. J Hypertens 30:1414–1422PubMedCrossRefGoogle Scholar
  81. 81.
    Terasawa K, Taguchi T, Momota R, Naito I, Murakami T, Ohtsuka A (2006) Human erythrocytes possess a cytoplasmic endoskeleton containing beta-actin and neurofilament protein. Arch Histol Cytol 69:329–340PubMedCrossRefGoogle Scholar
  82. 82.
    Clark MR, Mohandas N, Shohet SB (1983) Osmotic gradient ektacytometry: comprehensive characterization of red cell volume and surface maintenance. Blood 61:899–910PubMedCrossRefGoogle Scholar
  83. 83.
    Huisjes R, Bogdanova A, van Solinge WW, Schiffelers RM, Kaestner L, van Wijk R (2018) Squeezing for life—properties of red blood cell deformability. Front Physiol 9:656PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Mohandas N, Evans E (1994) Mechanical properties of the red cell membrane in relation to molecular structure and genetic defects. Annu Rev Biophys Biomol Struct 23:787–818PubMedCrossRefGoogle Scholar
  85. 85.
    Pesciotta EN, Sriswasdi S, Tang HY, Mason PJ, Bessler M, Speicher DW (2012) A label-free proteome analysis strategy for identifying quantitative changes in erythrocyte membranes induced by red cell disorders. J Proteomics 76:194–202PubMedCrossRefGoogle Scholar
  86. 86.
    Andolfo I, Russo R, Gambale A, Iolascon A (2016) New insights on hereditary erythrocyte membrane defects. Haematologica 101:1284–1294PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Tse WT, Lux SE (1999) Red blood cell membrane disorders. Br J Haematol 104:2PubMedCrossRefGoogle Scholar
  88. 88.
    Diez-Silva M, Dao M, Han J, Lim C, Suresh S (2010) Shape and biomechanical characteristics of human red blood cells in health and disease. MRS Bull 35:382–388PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Nigra AD, Monesterolo NE, Rivelli JF, Amaiden MR, Campetelli AN, Casale CH, Santander VS (2016) Alterations of hemorheological parameters and tubulin content in erythrocytes from diabetic subjects. Int J Biochem Cell Biol 74:109–120PubMedCrossRefGoogle Scholar
  90. 90.
    Machnicka B, Czogalla A, Hryniewicz-Jankowska A, Bogusławska DM, Grochowalska R, Heger E, Sikorski AF (2014) Spectrins: a structural platform for stabilization and activation of membrane channels, receptors and transporters. Biochim Biophys Acta 1838:620–634PubMedCrossRefGoogle Scholar
  91. 91.
    Sahr KE, Laurila P, Kotula L, Scarpa AL, Coupal E, Leto TL, Linnenbach AJ, Winkelmann JC, Speicher DW, Marchesi VT, Curtis PJ, Forget BG (1990) The complete cDNA and polypeptide sequences of human erythroid alpha-spectrin. J Biol Chem 265:4434–4443PubMedGoogle Scholar
  92. 92.
    Winkelmann JC, Chang JG, Tse WT, Scarpa AL, Marchesi VT, Forget BG (1990) Full-length sequence of the cDNA for human erythroid beta-spectrin. J Biol Chem 265:11827–11832PubMedGoogle Scholar
  93. 93.
    Speicher DW, Marchesi VT (1984) Erythrocyte spectrin is comprised of many homologous triple helical segments. Nature 311:177–180PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Liu SC, Derick LH, Palek J (1987) Visualization of the hexagonal lattice in the erythrocyte membrane skeleton. J Cell Biol 104:527–536PubMedCrossRefGoogle Scholar
  95. 95.
    Nans A, Mohandas N, Stokes DL (2011) Native ultrastructure of the red cell cytoskeleton by cryo-electron tomography. Biophys J 101:2341–2350PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Salomao M, Zhang X, Yang Y, Lee S, Hartwig JH, Chasis JA, Mohandas N, An X (2008) Protein 4.1R-dependent multiprotein complex: new insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci USA 105:8026–8031PubMedCrossRefGoogle Scholar
  97. 97.
    An X, Lecomte MC, Chasis JA, Mohandas N, Gratzer W (2002) Shear-response of the spectrin dimer-tetramer equilibrium in the red blood cell membrane. J Biol Chem 277:31796–31800PubMedCrossRefGoogle Scholar
  98. 98.
    Lux SE IV (2016) Anatomy of the red cell membrane skeleton: unanswered questions. Blood 127:187–199PubMedCrossRefGoogle Scholar
  99. 99.
    Lazarides E, Woods C (1989) Biogenesis of the red blood cell membrane-skeleton and the control of erythroid morphogenesis. Annu Rev Cell Biol 5:427–452PubMedCrossRefGoogle Scholar
  100. 100.
    Lehnert ME, Lodish HF (1988) Unequal synthesis and differential degradation of alpha and beta spectrin during murine erythroid differentiation. J Cell Biol 107:413–426PubMedCrossRefGoogle Scholar
  101. 101.
    Hanspal M, Palek J (1987) Synthesis and assembly of membrane skeletal proteins in mammalian red cell precursors. J Cell Biol 105:1417–1424PubMedCrossRefGoogle Scholar
  102. 102.
    Bogusławska DM, Machnicka B, Hryniewicz-Jankowska A, Czogalla A (2014) Spectrin and phospholipids—the current picture of their fascinating interplay. Cell Mol Biol Lett 19:158–179. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Ungewickell E, Bennett P, Calvert R, Ohanian V, Gratzer W (1979) In vitro formation of a complex between cytoskeletal proteins of the human erythrocyte. Nature 280:811–814PubMedCrossRefGoogle Scholar
  104. 104.
    Kalfa TA, Pushkaran S, Mohandas N, Hartwig JH, Fowler VM, Johnson JF, Joiner CH, Williams DA, Zheng Y (2006) Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood 108:3637–3645PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Chan MM, Wooden JM, Tsang M, Gilligan DM, Hirenallur-S DK, Finney GL, Rynes E, Maccoss M, Ramirez JA, Park H, Iritani BM (2013) Hematopoietic protein-1 regulates the actin membrane skeleton and membrane stability in murine erythrocytes. PLoS One 8:e54902PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Fowler VM, Bennett V (1984) Erythrocyte membrane tropomyosin. Purification and properties. J Biol Chem 259:5978–5989PubMedGoogle Scholar
  107. 107.
    Gardner K, Bennett V (1986) A new erythrocyte membrane-associated protein with calmodulin binding activity. Identification and purification. J Biol Chem 261:1339–1348PubMedGoogle Scholar
  108. 108.
    Franco T, Low PS (2010) Erythrocyte adducin: a structural regulator of the red blood cell membrane. Transfus Clin Biol 17:87–94PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Gauthier E, Guo X, Mohandas N, An X (2011) Phosphorylation dependent perturbations of the 4.1R-associated multiprotein complex of the erythrocyte membrane. Biochemistry 50:4561–4567PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Farag MR, Alagawany M (2018) Erythrocytes as a biological model for screening of xenobiotics toxicity. Chem Biol Interact 279:73–83PubMedCrossRefGoogle Scholar
  111. 111.
    Robertsson J, Petzold K, Lofvenberg L, Backman L (2005) Folding of spectrin’s SH3 domain in the presence of spectrin repeats. Cell Mol Biol Lett 10:595–612PubMedGoogle Scholar
  112. 112.
    Trave G, Lacombe PJ, Pfuhl M, Saraste M, Pastore A (1995) Molecular mechanism of the calcium-induced conformational change in the spectrin EF-hands. EMBO J 14:4922–4931PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Macias MJ, Musacchio A, Ponstingl H, Nilges M, Saraste M, Oschkinat H (1994) Structure of the pleckstrin homology domain frombeta-spectrin. Nature 369:675–677PubMedCrossRefGoogle Scholar
  114. 114.
    Rotter B, Kroviarski Y, Nicolas G, Dhermy D, Lecomte MC (2004) AlphaII-spectrin is an in vitro target for caspase-2, and its cleavage is regulated by calmodulin binding. Biochem J 378:161–168PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Ipsaro JJ, Huang L, Gutierrez L, MacDonald RI (2008) Molecular epitopes of the ankyrin–spectrin interaction. Biochemistry 47:7452–7464PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    van Deurs B, Behnke O (1973) The microtubule marginal band of mammalian red blood cells. Z Anat Entwicklungsgesch 143:43–47PubMedCrossRefGoogle Scholar
  117. 117.
    Bell AJ, Satchwell TJ, Heesom KJ, Hawley BR, Kupzig S, Hazell M, Mushens R, Herman A, Toye AM (2013) Protein distribution during human erythroblast enucleation in vitro. PLoS One 8:e60300PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Satchwell TJ, Bell AJ, Toye AM (2015) The sorting of blood group active proteins during enucleation. ISBT Sci Ser 10:163–168PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Xie S, Yan B, Feng J, Wu Y, He N, Sun L, Zhou J, Li D, Liu M (2019) Altering microtubule stability affects microtubule clearance and nuclear extrusion during erythropoiesis. J Cell Physiol 234:19833–19841PubMedCrossRefGoogle Scholar
  120. 120.
    Pasini EM, Mann M, Thomas AW (2010) Red blood cell proteomics. Transfus Clin Biol 17:151–164PubMedCrossRefGoogle Scholar
  121. 121.
    Goodman SR, Kurdia A, Ammann L, Kakhniashvili D, Daescu O (2007) The human red blood cell proteome and interactome. Exp Biol Med (Maywood) 232:1391–1408CrossRefGoogle Scholar
  122. 122.
    Goodman SR, Daescu O, Kakhniashvili DG, Zivanic M (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238:509–518CrossRefGoogle Scholar
  123. 123.
    Amaiden MR, Santander VS, Monesterolo NE, Campetelli AN, Rivelli JF, Previtali G, Arce CA, Casale CH (2011) Tubulin pools in human erythrocytes: altered distribution in hypertensive patients affects Na+, K+-ATPase activity. Cell Mol Life Sci 68:1755–1768PubMedCrossRefGoogle Scholar
  124. 124.
    Rivelli J, Amaiden M, Monesterolo N, Previtali G, Santander V, Fernandez A, Arce C, Casale C (2012) High glucose levels induce inhibition of Na, K-ATPase via stimulation of aldose reductase, formation of microtubules and formation of an acetylated tubulin/Na, K-ATPase complex. Int J Biochem Cell Biol 44:1203–1213PubMedCrossRefGoogle Scholar
  125. 125.
    Monesterolo N, Nigra A, Campetelli A, Santander V, Rivelli J, Arce C, Casale C (2015) PMCA activity and membrane tubulin affect deformability of erythrocytes from normal and hypertensive human subjects. Biochim Biophys Acta 1848:2813–2820PubMedCrossRefGoogle Scholar
  126. 126.
    Amaiden M, Santander V, Monesterolo N, Nigra A, Rivelli J, Campetelli A, Pie J, Casale C (2015) Effects of detyrosinated tubulin on Na+, K+-ATPase activity and erythrocyte function in hypertensive subjects. FEBS Lett 589:364–373PubMedCrossRefGoogle Scholar
  127. 127.
    Argaraña CE, Barra HS, Caputto R (1978) Release of [14C]tyrosine from tubulinyl-[14C]tyrosine by brain extract. Separation of a carboxypeptidase from tubulin-tyrosine ligase. Mol Cell Biochem 19:17–21PubMedCrossRefGoogle Scholar
  128. 128.
    Barra HS, Arce CA, Rodriguez JA, Caputto R (1973) Incorporation of phenylalanine as a single unit into rat brain protein: reciprocal inhibition by phenylalanine and tyrosine of their respective incorporations. J Neurochem 21:1241–1251PubMedCrossRefGoogle Scholar
  129. 129.
    Casale CH, Alonso AD, Barra HS (2001) Brain plasma membrane Na+, K+-ATPase is inhibited by acetylated tubulin. Mol Cell Biochem 216:85–92PubMedCrossRefGoogle Scholar
  130. 130.
    Lai L, Xu X, Lim CT, Cao J (2015) Stiffening of red blood cells induced by cytoskeleton disorders: a joint theory-experiment study. Biophys J 109:2287–2294PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ayelén D. Nigra
    • 1
    • 2
  • Cesar H. Casale
    • 1
  • Verónica S. Santander
    • 1
    Email author
  1. 1.Departamento de Biología Molecular, Facultad de Ciencias Exactas Físico-Químicas y NaturalesUniversidad Nacional de Río CuartoRío CuartoArgentina
  2. 2.Departamento de Química Biológica, Facultad de Ciencias Químicas, Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), UNC-CONICETUniversidad Nacional de CórdobaCórdobaArgentina

Personalised recommendations