Mammalian red blood cells lack a nucleus to maximize oxygen-carrying capacity
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The evidence confirms that mammalian red blood cells lack a nucleus, but the specific functional claim that this enucleation maximizes oxygen-carrying capacity is not established by the retrieved text.
The red blood cell or erythrocyte is easily purified, readily available, and has a relatively simple structure. Therefore, it has become a very well studied cell in terms of protein composition and function. RBC proteomic studies performed over the last five years, by several laboratories, have identified 751 proteins within the human erythrocyte. As RBCs contain few internal structures, the proteome will contain far fewer proteins than nucleated cells. In this minireview, we summarize the current knowledge of the RBC proteome, discuss alterations in this partial proteome in varied human disease states, and demonstrate how in silico studies of the RBC interactome can lead to considerable insight into disease diagnosis, severity, and drug or gene therapy response. To make these latter points we focus on what is known concerning changes in the RBC proteome in Sickle Cell Disease.
To make these latter points we focus on what is known concerning changes in the RBC proteome in Sickle Cell Disease. Exp Biol Med 232:1391–1408, 2007 Key words: red blood cell; erythrocyte; proteomics; interactome; systems biology; Sickle Cell Disease T he red blood cell (RBC) or erythrocyte travels through our circulatory system for 120 days, during which time it must constantly change its shape from a biconcave disc of 8 lm diameter to a cigar shape able to traverse passage ways that narrow to 1 lm in diameter.
A two dimensional meshwork of proteins called the spectrin membrane skeleton, found on the cytoplasmic surface of the plasma membrane, gives the RBC its properties of elasticity and flexibility that allows for the success of this journey (1– 5). Defects in this membrane skeleton lead to misshapen and osmotically fragile RBCs (6–10). This tortuous journey traveled by the erythrocyte is for the purpose of carrying oxygen from our lungs to cells, tissues and organs throughout the body; and returning carbon dioxide to our lungs. This essential RBC function is conducted by hemoglobin, the major protein constituent of the RBC cytosol.
The erythrocyte is the simplest of human cells as it lacks internal organelles; lost during the process of erythropoiesis. The ease of obtaining blood, lack of internal organelles, and important physiologic function of the RBC has made it a major focus of biochemical study during the 20th and 21st century. As a result, we know the functions of erythrocyte proteins in greater detail than any other human cell type. The simplicity of the human erythrocyte cell structure has also made it an optimal cell for proteomic study. While nucleated cells contain 20,000 to 30,000 proteins (11–14), RBCs which lack nuclei and other organelles contain far fewer.
As mature Red Blood Cells are thought not to synthesize nascent proteins only the latter function is relevant to this discussion. The ROD box also contains proteins involved in Figure 1b. THE HUMAN RBC PROTEOME AND INTERACTOME 1401 at SAGE Publications on November 18, 2014ebm.sagepub.comDownloaded from the proteasomal degradation of ubiquitinated proteins (ex proteasomal subunits). The recent demonstration, by our laboratory (18), that proteasomes are present in mature RBCs raises the important question of whether ubiquitin dependent proteolytic degradation exists in RBCs.
The American Journal of Physiology 244(3):C121–141, 1983. 2. Goodman SR, Krebs KE, Whitfield CF, Riederer BM, Zagon IS. Spectrin and related molecules. CRC Critical Reviews in Biochemistry 23(2):171–234, 1988. 3. Bennett V, Lambert S. The spectrin skeleton: From red cells to brain. Journal of Clinical Investigation 87(5):1483–1489, 1991. 4. Hsu YJ, Goodman SR. Spectrin and ubiquitination: A review. Cellular and Molecular Biology (Noisy-Le-Grand, France) Suppl 51:OL801– 807, 2005. 5. Dhermy D, Schreı `vel J, Lecomte M-. Spectrin-based skeleton in red blood cells and malaria. Current Opinion in Hematology 14(3):198– 202, 2007. 6. Palek J, Sahr KE.
Proteomic analysis of erythrocyte membranes by soft immobiline gels combined with differential protein extraction. Journal of Proteome Research 4(4): 1304–1309, 2005. 21. Pasini EM, Kirkegaard M, Mortensen P, Lutz HU, Thomas AW, Mann M. In-depth analysis of the membrane and cytosolic proteome of red blood cells. Blood 108(3):791–801, 2006. 22. Chaurasia G., Iqbal, Y., Ha ¨nig, C., Herzel, H., Wanker, E. and Futschik, M. UniHI: an entry gate to the human protein interactome, Nucleic Acids Res. 35 Database issue:D590–604, 2007. 23. Balasubramanian, R., LaFramboise, T., Scholtens, D., and Gentleman, R.
A graph theoretic approach to testing associations between disparate sources of functional genomics data. Bioinformatics, 20, 3353–3362, 2004. 24. R Development Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0. URL http://www.R-project.org, 2007. 25. Csardi, G. igraph: Routines for simple graphs, network analysis. R package version 0.3.3. URL: http://cneurocvs.rmki.kfki.hu/igraph, 2006. 26. Jiang M, Jia L, Jiang W, Hu X, Zhou H, Gao X, Lu Z, Zhang Z. Protein disregulation in red blood cell membranes of type 2 diabetic patients.
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Florens L, Liu X, Wang Y, Yang S, Schwartz O, Peglar M, Carucci DJ, Yates III JR, Wu Y. Proteomics approach reveals novel proteins on the surface of malaria-infected erythrocytes.
their develop- ment, mammalian red blood cells lose their nuclei. With- out a nucleus, the cell cannot divide … single molecule of he- moglobin, the oxygen-carrying protein in red blood cells, exhibits all four structural … represented here by hemoglobin, the oxygen-carrying protein in red blood cells (the red discs represent the
Physiological activity in healthy conditions requires a coordinated interaction between the molecular circadian clock and the network of biochemical pathways. An important metabolic parameter in the interface between these two entities is the redox state. Among the redox coenzymes that regulate the fluxes of enzymatic reactions is the NADP+/NADPH pair. Indeed, the main biosynthetic pathways need NADPH to serve as an electron donor for cellular anabolic transformations. The existence of a metabolic circadian clock is well established, and it was first identified in mammalian red blood cells. The metabolic circadian clock is independent of transcriptional activity and is sustained by the enzymatic complex peroxiredoxin/thioredoxin/NADPH. This complex shows 24-h redox fluctuations metabolizing H2O2 in various tissues and species (fungi, insects, and mammals). Although this NADPH-sensitive metabolic clock is autonomous in erythrocytes that lack a nucleus, it functions in concert with the transcriptional circadian clock in other cell types to accomplish the task of timing cellular physiology. During carcinogenesis, circadian alterations influence cell cycle onset and promote tumoral growth. These alterations also deregulate cellular energetics through a process known as aerobic glycolysis, or the Warburg effect. The Warburg effect is a typical response of cancer cells in which the metabolism turns into glycolysis even in the presence of functional mitochondria. This alteration has
An important metabolic parameter in the interface between these two entities is the redox state. Among the redox coenzymes that regulate the fluxes of enzymatic reactions is the NADP + /NADPH pair. Indeed, the main biosynthetic pathways need NADPH to serve as an electron donor for cellular anabolic transformations. The existence of a metabolic circadian clock is well established, and it was first identified in mammalian red blood cells. The metabolic circadian clock is independent of transcriptional activity and is sustained by the enzymatic complex peroxiredoxin/thioredoxin/NADPH.
This complex shows 24-h redox fluctuations metabolizing H 2 O 2 in various tissues and species (fungi, insects, and mammals). Although this NADPH-sensitive metabolic clock is autonomous in erythrocytes that lack a nucleus, it functions in concert with the transcriptional circadian clock in other cell types to accomplish the task of timing cellular physiology. During carcinogenesis, circadian alterations influence cell cycle onset and promote tumoral growth. These alterations also deregulate cellular energetics through a process known as aerobic glycolysis, or the Warburg effect.
Reddy’s laboratory while studying human red blood cells (without nuclei in their mature form) ( 3 ). They reported the presence of a metabolic circadian oscillator based on the redox cycle of peroxiredoxin enzymes ( 4 ). Peroxiredoxins belong to a family of antioxidant enzymes whose main function is the catabolic degradation of hydrogen peroxide by controlling its levels and the associated signaling events ( 5 ). Peroxiredoxins are localized in several subcellular organelles.
Under physiological conditions, the actual oxidation-reduction potential depends on the levels and ratio of the concentrations of the individual members of the redox couple, as well as on the prevalent pH. Each redox pair shows a defined ratio between its elements (reduced/oxidized) according to their subcellular compartments. The complete set of redox pairs makes up the global cellular redox state, a parameter that dictates the unique pattern of electron flux for any cell system.
In addition, NADPH acts as an electron donor for the reductive formation of lipid molecules (cholesterol and fatty acids) and nucleic acids. It is a cofactor for O 2 − generation during NADPH oxidase activity and a protector of mitochondrial DNA integrity. NADPH also acts as a nuclear modulator of gene expression by promoting redox signaling within the nucleus. Finally, it has been shown that NADPH, as a product of the pentose phosphate pathway (PPP), is able to modulate circadian rhythms by extending or shortening the 24-h fluctuations in human cells, mouse tissues, and fruit flies ( 13 ).
In fact, a hyperoxidized form of peroxiredoxin III and sulfiredoxin is in antiphase circadian oscillation in healthy cells ( 25 ). Overexpression of peroxiredoxins with a decrease in sulfiredoxin in some neoplasias correlates with poor prognosis ( 26 ). However, it is not known if overexpression of peroxiredoxins is due to changes in a rhythmic profile of activation by NADPH that contribute to tumor development in a protective redox role of peroxiredoxins.
The rationale of the Warburg effect in oncology is that cancerous cells are programmed for high cellular proliferation; hence, the continuous entry into the cell cycle involves a constant input of new molecules for the synthesis of biological membranes, genetic material, and all the cellular elements needed for the newly formed tumoral cells ( 32 ). This anabolic commitment is fulfilled by an upgraded availability of NADPH during neoplastic growth, since this coenzyme is required by the
This enzyme allows the formation of nicotinamide adenine dinucleotides; however, the redox state is necessarily defined by the ratio of the redox couple (reduced/oxidized) ( 40 ). Indirectly, the reduced role of PPARγ in cancerous cells ( 31 ) could be associated with the damped circadian rhythms mentioned in the previous section. Specifically, there are few reports on circadian regulation of the enzymes responsible for NADPH availability during the Warburg effect, and almost none regarding their daily rhythms in cancerous cells or tumors.
As an exception, the activity of the PPP, one of the major generators of NADPH, has been recognized as an element of circadian physiology in various cell systems ( 13 ). Summary The conceptual message of this minireview is outlined in Figure 1 .
It has been known for more than 130 years that mammalian red cells lack a nucleus and, thus, differ fundamentally from the red cells of fish, birds, and reptiles that maintain their nucleus caged in a network of intermediate filaments. However, the process of erythroblast enucleation has remained provocative and poorly understood.In this issue of Blood, Konstantinidis et al provide evidence that erythroblast enucleation is a more complex and multistep process than previously thought, involving sequential actions of tubulin and filamentous actin, as well as lipid raft formation
Blood smear from a bird showing the prolific nucleated red blood cells and a variety of white blood cells. The small, compact, purple-stained cell is a thrombocyte, the larger pinky purple cell is a heterophil and the large purple cell is likely to be a basophil. Bird red blood cells differ from mammalian red blood cells by retaining their nuclei. The sample has been stained with haemotoxylin (purple) and eosin (pink)
Blood smear from a bird showing the prolific nucleated red blood cells and a variety of white blood cells. The small, compact, purple-stained cell is a thrombocyte, the larger pinky purple cell is a heterophil and the large purple cell is likely to be a basophil. Bird red blood cells differ from mammalian red blood cells by retaining their nuclei. The sample has been stained with haemotoxylin (purple) and eosin (pink)
It has been reported that: (1) large variations were found in the number of sialic acid (SA) capped with N-acetyllactosamines (SA-Galbeta1-4GlcNAc-R) and alpha-Gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R) or uncapped N-acetyllactosamines (Galbeta1-4GlcNAc-R) on different mammalian red blood cells, and on nucleated cells originating from a given tissue in various species; (2) goat, sheep, horse and mouse red blood cells lack alpha-Gal epitopes, despite the expression of this epitope on a variety of nucleated cells in these species, including lymphocytes differentiated from the same hematopoietic origin. In this study, flow cytometry and Western blot analyses of pig red blood cells showed that alpha-Gal epitopes on pig red cells developed concomitantly after treatment with neuraminidase, suggesting that the terminal N-acetyllactosaminide glycans were capped with SA-alpha-Gal epitopes. Whereas, the expression of the alpha-Gal epitopes on red blood cells from Sika deer (Cevus nippon hortulorum) were found to be absent even though the epitopes were present on their white blood cells. Thus, these results add new data not only for the terminal carbohydrate structures on cell surface glycans of various mammalian cells, but also for wide variety of epitope expression on the cells from different tissues, which might be useful for understanding their unique states resulting from differentiation and evolution.
Brief report: a new profile of terminal N-acetyllactosamines glycans on pig red blood cells and different expression of α-galactose on Sika deer red blood cells and nucleated cells | Glycoconjugate Journal | Springer Nature Link Skip to main content Brief report: a new profile of terminal N -acetyllactosamines glycans on pig red blood cells and different expression of α-galactose on Sika deer red blood cells and nucleated cells Published: 27 April 2010 Volume 27 , pages 427–433 ( 2010 ) Cite this article Save article View saved research Glycoconjugate Journal Aims and scope Submit manuscript Abstract It has been reported that: (1) large variations were found in the number of sialic acid (SA) capped with N -acetyllactosamines (SA-Galβ1-4GlcNAc-R) and α-Gal epitopes (Galα1-3Galβ1-4GlcNAc-R) or uncapped N -acetyllactosamines (Galβ1-4GlcNAc-R) on different mammalian red blood cells, and on nucleated cells originating from a given tissue in various species; (2) goat, sheep, horse and mouse red blood cells lack α-Gal epitopes, despite the expression of this epitope on a variety of nucleated cells in these species, including lymphocytes differentiated from the same hematopoietic origin.
In this study, flow cytometry and Western blot analyses of pig red blood cells showed that α-Gal epitopes on pig red cells developed concomitantly after treatment with neuraminidase, suggesting that the terminal N -acetyllactosaminide glycans were capped with SA-α-Gal epitopes. Whereas, the expression of the α-Gal epitopes on red blood cells from Sika deer ( Cevus nippon hortulorum ) were found to be absent even though the epitopes were present on their white blood cells.
Antibodies Glycobiology Glycomics Glycoproteins Lectins Plasma cells Glycosylation Mechanisms in Cancer Biology Abbreviations α-Gal: Galα1-3Galβ1-4GlcNAc FACS: Fluorescent activated cell sorting FCM: Flow cytometry FITC: Fluorescein isothiocyanate GlcNAc: N -acetylglucosamine GS-IB4: Griffonia simplicifolia isolectin B4 hRBC-A and hRBC-O: Group A and O of human red blood cell M86: Mouse monoclonal antibody to α-gal epitopes NeuGc: N -glycolylneuraminic acid N -acetyllactosamine: Galβ1-4GlcNAc-R PBS: Phosphate buffered saline PK15: Pig kidney cell line PVDF: Polyvinyidene fluoride SA: Sialic acid TBST: Tris-buffered saline, 0.1% Tween 20 References Galili, U., Clark, M.R., Shohet, S.B., Buehler, J.,
Proc. Natl. Acad. Sci. USA 94 , 14677–14682 (1997) Article PubMed CAS Google Scholar Cooper, D.K.C.: Alpha1, 3-Galactosyltransferase gene-knockout was an essential step towards successful pig organ transplantation in primates. Xenotransplantation 14 , 182–183 (2007) Article Google Scholar Rouhani, F.J., Dor, F.J.M.F., Cooper, D.K.C.: Investigation of red blood cells from α1, 3-galactosyltransferase knockout pigs for human blood transfusion. Transfusion 44 , 1004–1012 (2004) Article PubMed Google Scholar Eckermann, J.M., Buhler, L.H., Zhu, A., Dor, F.J.M.F., Awwad, M., Cooper, D.K.C.: Initial investigation of the potential of modified porcine erythrocytes for transfusion in primates.
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Rights and permissions Reprints and permissions About this article Cite this article Tan, Y., Gong, F., Li, S. et al. Brief report: a new profile of terminal N -acetyllactosamines glycans on pig red blood cells and different expression of α-galactose on Sika deer red blood cells and nucleated cells. Glycoconj J 27 , 427–433 (2010).
Copy shareable link to clipboard Provided by the Springer Nature SharedIt content-sharing initiative Keywords Pig red blood cell α-Gal epitope Sialic acid N -acetyllactosamine α-Galactosidase Neuraminidase Sika deer blood cell Access this article Log in via an institution Subscribe and save Springer+ from €37.37 /Month Starting from 10 chapters or articles per month Access and download chapters and articles from more than 300k books and 2,500 journals Cancel anytime View plans Buy Now Buy article PDF 39,95 € Price includes VAT (Indonesia) Instant access to the full article PDF. Institutional subscriptions Advertisement
Whereas mature red blood cells lack a nucleus, immature red blood cells do have a nucleus, and they have … three formed elements: red blood cells, white blood cells, and platelets. Red blood cells are small, biconcave … elements are red blood cells, white blood cells, and platelets. Among the formed elements, red blood cells,
as red cells, erythroid cells, and rarely haematids, are the most common type of blood cell and the vertebrate's principal means of delivering oxygen (O2)
Red blood cells (RBCs), referred to as erythrocytes (from Ancient Greek erythros 'red' and kytos 'hollow vessel', with -cyte translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cell and the vertebrate's principal means of delivering oxygen (O2) to the body tissues—via blood flo
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The red blood cells of mammals are typically shaped as biconcave disks: flattened and depressed in the center, with a dumbbell-shaped cross section, and a torus-shaped rim on the edge of the disk. This shape allows for a high surface-area-to-volume (SA/V) ratio to facilitate diffusion of gases. However, there are some exceptions concerning shape in the artiodactyl order (even-toed ungulates including cattle, deer, and their relatives), which displays a wide variety of bizarre red blood cell morphologies: small and highly ovaloid cells in llamas and camels (family Camelidae), tiny spherical cells in mouse deer (family Tragulidae), and cells which assume fusiform, lanceolate, crescentic, and irregularly polygonal and other angular forms in red deer and wapiti (family Cervidae). Members of this order have clearly evolved a mode of red blood cell development substantially different from the mammalian norm. Overall, mammalian red blood cells are remarkably flexible and deformable so as to squeeze through tiny capillaries, as well as to maximize their apposing surface by assuming a cigar shape, where they efficiently release their oxygen load.
Red blood cells in mammals are unique amongst vertebrates as most species do not have nuclei when mature. They do have nuclei during early phases of erythropoiesis, but extrude them during development as they mature; this provides more space for hemoglobin. The red blood cells without nuclei, called reticulocytes, subsequently lose all other cellular organelles such as their mitochondria, Golgi apparatus and endoplasmic reticulum.
The spleen acts as a reservoir of red blood cells, but this effect is somewhat limited in humans. In some other mammals such as dogs and horses, the spleen sequesters large numbers of red blood cells, which are dumped into the blood during times of exertion stress, yielding a higher oxygen transport capacity.
Anemias (or anaemias) are diseases characterized by low oxygen transport capacity of the blood, because of low red cell count or some abnormality of the red blood cells or the hemoglobin.
Iron deficiency anemia is the most common anemia; it occurs when the dietary intake or absorption of iron is…
TWO MEN FOUND WITH FISH BLOOD Elliptical Blood Cells May Be ι ThrowBack to Lower Forms BY THOMAS R HENRY Some men have fish blood A strange human anomaly which tnay bf a throwbark over millions of fenerations to the fishes and reptiles Is reported In the current Issue of the medical bulletin of the Veterans Ad ministration Two cases of veterans treated at Government hospitals whose red blood cells at least in part were elliptical Instead of circular in shapean aston ishing variation from the biological standpointare cited by Drs M C Terry E W Hollingsworth and Vin cent Eugenio of the Veterans Admin istration staff This is a condition they point out hich is almost entirely absent in the whole race of mammals from the half reptile egglaying platypus of Aus tralia to man himself On the other hand it is the characteristic condi tion amorg the lower vertebrates such as the fishes amphibians and reptiles The change in the shape of the red blood cells occurred somewhere in the process of transition from the lower to the higher verterbrates more than a hundred million years ago but appar ently a tiny strain of the reptilelike blood has
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