PRELI, the human homologue of the avian px19, is expressed by germinal center B lymphocytes
Liliana Guzman-Rojas,
Jennifer C. Sims,
Roberto Rangel,
Christiane Guret1,
Yan Sun,
Juan M. Alcocer2 and
Hector Martinez-Valdez
Department of Immunology, Box 178, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
1 Schering-Plough, Laboratory for Immunological Research, 27 Chemin des Peupliers, 69571 Dardilly Cedex, France
2 Department of Immunology, School of Biological Sciences, Universidad Autonoma de Nuevo Leon, Monterrey, NL, Mexico
Correspondence to:
H. Martinez-Valdez
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Abstract
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We report the identification of a human cDNA encoding a 25 kDa protein of relevant evolutionary and lymphoid interest (PRELI). PRELI was cloned by screening a B lymphocyte-specific cDNA library with a probe generated by mRNA differential display. PRELI amino acid sequence is 85% similar to the avian px19 protein, expressed within the blood islands and in the liver during avian embryo development. PRELI and px19 contain tandem repeats (A/TAEKAK) of the late embryogenesis abundant (LEA) motif, characteristic of a group of survival molecules and originally thought to be present only in plant proteins. Interestingly, PRELI expression is high in the fetal liver, a major site for B cell lymphopoiesis, while the mRNA levels in other fetal tissues such as the brain, lung, and kidney are comparatively low. At the adult stage, PRELI expression is drastically reduced in the liver but exhibits high mRNA levels in the spleen, brain, lung and kidney tissues, suggesting that PRELI expression may be important for the development of vital and immunocompetent organs. Moreover, PRELI is also highly expressed in the adult lymph nodes and peripheral blood leukocytes, further stressing that at the adult stage, PRELI expression may be important during secondary immune responses. Consistent with this hypothesis, the expression of PRELI is predominant within germinal centers (GC), a stage in which B lymphocytes are under a stressful selection pressure. Taken together these data: (i) strongly support the notion that the conserved LEA motif represents a phylogenetic link between plants and animals, (ii) reveal a novel molecule whose expression may play a role in the maturation of distinct human tissues, and (iii) suggest that PRELI expression may be important for GC B lymphocytes.
Keywords: B lymphocytes, cDNA cloning, germinal centers, LEA motif, phylogeny
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Introduction
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Developing seeds in plants are subjected to extreme stress conditions and, like in animals, the ability of the plant cells to survive such stressful selection pressure relies on the expression of survival proteins (1,2). Proteins containing the late embryogenesis abundant (LEA) motif act as desiccation protectants during seed germination and against most types of stress affecting plant embryo development (3,4). LEA proteins are present in most plants as a gene family and exhibit a high amino acid sequence conservation among family members (5,6). LEA protein expression is high in seed embryos and is thought to play a survival role in desiccation tolerance by acting as protectors of cell osmolarity or as desiccation-damage repair proteins. In agreement with the cell survival function, LEA protein synthesis is also induced in salt and temperature-stressed seedlings (7). Because the control of osmolarity, pH, ionic strength and temperature may also represent mechanisms through which non-plant organisms may regulate survival during stressful cell selection pressure, it could be anticipated that LEA motif-containing proteins might be evolutionarily conserved in animals. Consistent with that prediction, Niu et al. (8) have cloned px19, an avian cDNA encoding the first vertebrate homologue of the LEA motif-containing proteins. px19 appears to be developmentally regulated, and its expression is high within the blood islands in the area opaca and in the liver primordia, in a timely manner that correlates with hematopoiesis during chick embryo development.
Our laboratory studies human hematopoietic development (912), focusing on critical stage-specific functions during B lymphocyte differentiation and activation (1316). As is well established, the B lymphocyte maturation program within the bone marrow achieves several goals: (i) a continuous output of large numbers of B lymphocytes, (ii) their development into immature surface IgM+ B cells (17) and (iii) their selection to enter the long-lived mature B cell pools. The need to understand the molecular mechanisms that control B lymphocyte maturation and differentiation (13,18) led us to hypothesize the existence of stage-specific genes, differentially expressed during mature B lymphocyte differentiation and selection. The present work reports the discovery of a human cDNA, encoding a 25 kDa protein which exhibits the LEA motif (A/TAEKAK) repeat found in plants and birds. The protein has been named PRELI, because of its relevant evolutionary leap from plants to humans and its potential biological significance in lymphoid physiology. Lastly, this study demonstrates that PRELI is the human homologue of the avian px19 molecule.
To investigate the existence of stage-specific molecules differentially expressed during mature B lymphocyte differentiation, we combined a cellular and a molecular approach. First, B lymphocyte subsets were isolated as previously described (14) and according to institutional guidelines. Briefly, tonsillar B lymphocyte sub-populations were purified by FACS into five distinct subsets: IgD+CD38CD23 (Bm1) + IgD+CD38CD23+ (Bm2) naive, IgDCD38+CD77+ (Bm3) + IgDCD38+CD77 (Bm4) germinal center (GC) and CD38IgD (Bm5) memory B lymphocytes. Cells were routinely sorted to a 9798% purity. Second, a gene family-targeting method for RT-PCR differential display (19) was devised, by designing primers based on known gene family motifs: (i) cell survival-related molecules, (ii) proteins displaying death domain sequences and (iii) molecules with transcription factor motifs. Quasi-consensus sequences were examined by shot-gun alignment and degenerate oligonucleotide primers were designed. Gene family motif-targeted RT-PCR differential display was carried out by the amplification of total RNA obtained from 500 cells of each one of the FACS-sorted mature B cell (Bm1Bm5) subsets (14). Twelve differentially expressed PCR products were identified by this procedure (data not shown). The differentially amplified PCR products were gel purified and sequenced (University of Texas MD Anderson Cancer Center Sequencing Core Facility).
Comparative analysis of the 12 cDNA clones was performed, against the non-redundant database at the National Center for Biotechnology Information (NCBI) of the National Library of Medicine, using the Blast-N and P algorithm sequence similarity programs (20). By this analysis, it was found that seven out of the 12 clones belonged to known gene families and corresponded to previously reported molecules. PRELI was among the five novel cDNA clones and was chosen for further characterization.
Amplified PRELI fragment was used as probe to obtain the full-length cDNA from a conventional human library. To that end, a B lymphocyte-specific library was constructed and screened by standard procedures. Briefly, poly(A)+ was prepared from freshly isolated tonsillar B lymphocytes using the poly(A)+ track kit (Invitrogen, Palo Alto, CA). cDNA was synthesized, size selected and cloned into the pSPORT vector using the Superscript II cDNA cloning kit (Life Technologies, Gaithersburg, MD) according to the manufacturer's specifications. The library was screened using a 32P-labeled PRELI probe, and a relevant cDNA clone was isolated, purified and automatically sequenced.
PRELI cDNA contained a 1.0 kb insert, exhibiting an open reading frame of 219 amino acids which predicted a protein of 25 kDa (Fig. 1
). Full-length PRELI sequence comparison against the non-redundant nucleotide and amino acid databases at NCBI was reassessed and revealed that PRELI is the human homologue of the avian px19 protein (8). px19 was identified as a BrdU-sensitive 0.9 kb transcript by a subtraction hybridization procedure. px19 encodes a 23 kDa protein, whose timely expression correlates with the stage in which hematopoiesis is observed during avian development. Alignment of PRELI and px19 revealed that analogous to px19, PRELI exhibited the tandem repeat LEA motif (A/TAEKAK), originally thought to be present only in plants (3,4,21).

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Fig. 1. PRELI is the human homologue of the avian px19 protein. px19 amino acid sequence was retrieved from the non-redundant database at the NCBI of the National Library of Medicine, using the Blast-N and P algorithm sequence similarity programs (16). A two-protein alignment analysis comparing PRELI and px19 was performed, using either the Jotun Hein or the Clustal methods of Megalign software from the Lasergene file (DNASTAR, Madison, WI). Irrespective of the number of sequences, either procedure executes the alignment based on a consensus created by the program to give an equal value to the aligned sequences and automatically introduces gaps to report the greatest sequence identity. The numbering of the sequence therefore corresponds to the program-derived contig. Predicted amphipathic helices containing tandem repeats of the LEA motif are boxed. Nucleotide and amino acid sequences have been deposited at NCBI and given Bankit no. 301469 (accession number AF201925).
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As shown in Fig. 1
, the similarity between the avian px19 and PRELI was beyond the conserved LEA motif, with an overall 85% amino acid sequence identity. Both avian and human protein sequences display two
helices with amphipathic domains in opposite orientation, and within this region LEA motif repeats are clustered. The molecular cloning of the avian px19 (8) provided the first evidence of the evolutionary conservation of LEA motif-containing proteins in vertebrates. Although the precise function of px19 has not been determined, its expression within the sites and at the time in which blood cells are generated suggest a potential role in hematopoiesis. The discovery of PRELI confirms the significance of the evolutionary conservation of LEA proteins and further extends its phylogenetic leap from birds to humans.
Because of the high degree of sequence conservation between PRELI and px19, and because of the potential association of px19 to hematopoietic organs, we sought to examine the expression of PRELI in fetal and adult tissues. To that end, multiple tissue Northern blots were commercially obtained (Clontech Laboratories, Palo Alto, CA or Invitrogen, Carlsbad, CA) and hybridized according to the methods recommended by manufacturer. Alternatively, Northern blots were generated in the laboratory as previously reported (23) using 5 or 10 µg of total unfractionated RNA. Northern blots were hybridized using 32P-labeled PRELI cDNA probe, stringently washed and subsequently autoradiographed. As shown in Fig. 2(A)
, PRELI expression at the fetal stage was predominant in the liver, while in other organs, such as the brain, kidney and lungs, the expression remained significantly low. This is an interesting observation because fetal liver is a major hematopoietic organ during fetal life and the most important site for B cell lymphopoiesis. These results together with the recent observation that PRELI is timely expressed in the yolk sac of the mouse embryo (L. Guzman-Rojas, unpublished results) suggest that the expression of PRELI may play a significant role in hematopoiesis and lymphopoiesis during embryo and fetal life.

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Fig. 2. mRNA expression of PRELI. (A) Human fetal multiple tissue Northern blot (Clontech) analysis was carried out, to examine the expression of PRELI by normal fetal tissues. (B) Expression of PRELI by counterpart adult tissues (Invitrogen). (C) Expression of PRELI within immunocompetent organs (Clontech). The levels and molecular size of PRELI mRNA were determined by hybridization of the commercially obtained blots to a 32P-labeled PRELI cDNA probe, following the instructions of the manufacturer. The Northern blots were stringently washed and exposed to X-ray films, which were subsequently developed after an overnight exposure at 70°C. Lanes specifically identify the examined tissues. A predominant 1.0 kb molecular species corresponding to the cloned PRELI cDNA is indicated. Northern blots obtained from Clontech (A and C) have been ß-actin normalized by the manufacturer to control for equal RNA distribution. The blot in (B) is herein controlled by the constitutive expression of the human ribosomal protein S9.
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It is noteworthy that a 1.0 kb mRNA corresponding to the size of the cloned cDNA was the predominant transcript. However, a higher molecular size (~1.2 kb) was also observed. Our cDNA screening did not detect the weakly expressed 1.2 kb species, likely due to its lower representation in our mature B lymphocyte library. It remains to be determined whether the 1.2 kb mRNA results from an alternative splicing mechanism or if it represents a unique but related PRELI molecule expressed by other non-lymphoid cell lineages.
Because the expression of PRELI at the fetal stage may be simply the result of tissue-associated expression and not necessarily a developmental involvement, a comparative expression analysis in the counterpart adult tissues was carried out. Figure 2(B)
shows that in contrast to the fetal expression, PRELI mRNA was drastically reduced in the adult liver. Conversely, PRELI expression in the adult brain, kidney, lung and spleen was significantly high. PRELI expression in other adult organs such the heart, pancreas and skeletal muscle was either unremarkable or absent. Together, these findings suggest that PRELI expression may play a significant developmental role: (i) important for the postnatal maturation of vital organs such as the brain, lung and kidney, and (ii) critical for the maturation and differentiation of immunocompetent cells during both fetal and adult life.
In order to investigate the significance of PRELI expression within the immune system, a Northern blot analysis was carried out using a commercial blot containing fetal and adult tissues. Figure 2(C)
shows that in agreement with the findings in Fig. 2(A)
, PRELI expression was consistently high in the fetal liver. At the adult stage, PRELI expression was high in the spleen, lymph node and peripheral blood leukocytes, whereas it was extremely low in the bone marrow and the thymus. These results suggest that PRELI expression may be more important for B than for T lymphocyte differentiation. Furthermore, the results in Fig. 2(C)
also suggest that PRELI expression may be equally important during the first wave of B cell lymphopoiesis at the fetal stage and during antigen-dependent B lymphocyte differentiation within adult secondary lymphoid organs.
To investigate the relevance of PRELI expression at different stages of B lymphocyte maturation Northern blot analysis was carried out using established B cell lines which phenotypically resemble distinct differentiation stages. Figure 3
shows that consistent with the low PRELI mRNA levels observed in the bone marrow, no detectable expression by B cell progenitors (pro-B) and precursors (pre-B) was observed. In contrast, mature B cells expressed significant levels of PRELI mRNA. These results are in agreement with the findings depicted in Fig. 2(C)
and further support our hypothesis that in the adult, PRELI expression may be more significant for mature B lymphocyte during secondary immune responses.

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Fig. 3. Expression of PRELI by cell lines representing discreet stages of B lymphocyte development. Total unfractionated RNA was isolated from various leukemic cell lines that have been phenotypically characterized and display surface markers of distinct stages of B cell development (2429). RNA was electrophoresed, Northern blotted and hybridized to 32P-labeled PRELI cDNA. The blot was stringently washed and autoradiographed after an overnight exposure at 70°C. (A) Depicts the results of the hybridization and (B) shows the ethidium bromide-stained gel to monitor sample loading.
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Although the results of PRELI stage-specific expression by B lymphocytes (Fig. 3
) correlate with a predominant expression within secondary lymphoid organs (shown in Fig. 2C
), the stage-specific analysis is based in single cell lines and cannot rule out cell line idiosyncrasy. Therefore, in order to rule out cell line idiosyncrasy and further substantiate the hypothesis that the expression of PRELI is associated with mature B lymphocyte stage-specific phenotype, RNA from pure mature B lymphocyte subsets was isolated and analyzed by Northern blotting. Briefly, tonsillar B lymphocytes were FACS-purified into three major mature B cell subsets (Fig. 4A
): Bm1 + Bm2 (IgD+CD38) naive, Bm3 + Bm4 (IgDCD38+) GC and Bm5 (IgDCD38) memory cells, as previously reported (14). Total RNA (5 µg) from each subset was electrophoresed, transferred and hybridized to 32P-labeled PRELI cDNA probe. The Northern blot was stringently washed and autoradiographed. Figure 4
shows that PRELI is predominantly expressed by GC B lymphocytes, suggesting that analogous to the survival function of plant LEA proteins for the developing embryo, PRELI may play a cell protective role during a stage in which B lymphocytes are under a stressful selection pressure.

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Fig. 4. Expression of PRELI by GC B lymphocytes. (A) FACS scheme used for purification tonsillar B cell subsets. Cells were double stained with a FITC-conjugated mouse anti-human IgD (PharMingen, San Diego, CA) and phycoerythrin-conjugated mouse anti-human CD38 (Becton Dickinson, San Jose, CA). Corresponding stained subsets are herein indicated. (B) Northern blot analysis using 5 µg of total RNA from each naive (Bm1 + Bm2), GC (Bm3 + Bm4) and memory (Bm5) mature B lymphocyte subsets. RNA was electrophoresed, Northern blotted and hybridized to 32P-labeled PRELI cDNA. The blot was stringently washed and autoradiographed after an overnight exposure at 70°C. The human ribosomal protein S9 was used as an internal control.
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Plants respond to numerous types of stresses which include drought, extreme pH and salt concentration, and abrupt changes in temperature by the induction of expression of survival proteins (16). The diversity of microenvironmental and developmental selection pressure controls affecting plant embryo development implies the existence of multiple LEA protein signals feeding into a common regulatory pathway. Such a common mechanism can, in turn, induce resistance to a variety of stresses imposed by the tight selection pressure during plant development. LEA proteins are critical during seed germination and embryo development as they protect plants from most types of stresses affecting the embryo (21,22). Analogous to animal organisms, LEA proteins together with the anti-freeze molecules constitute a family of survival proteins whose function is to protect developing cells. Thus, the stage-specific expression of the LEA motif proteins during plant embryogenesis and the critical nature of their function could anticipate that LEA motif-containing proteins might have been evolutionarily conserved into non-plant species. The discovery of LEA motif-containing px19 (8) in birds and PRELI in the humans (reported herein) confirms this prediction, and strongly suggest the existence of other survival mechanisms which may also operate in animal cells. In this context, LEA-protein-mediated stress tolerance may be important for the way that animal cells manage strong selection pressures. Particularly for mature B lymphocytes, LEA protein-like stress-tolerance mechanisms might be critical, as B lymphocytes are known to undergo stressful selection pressure during maturation and differentiation within GC of secondary lymphoid organs.
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Acknowledgments
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We thank Drs Miles F. Wilkinson and Fernando Lopez-Casillas for critically reviewing the manuscript. We are grateful to Dr Tucker LeBein for providing the cell lines Nalm 16 and Biln-1, and Dr Mitsufumi Mayumi for providing the cell line B104. This work was supported by the grant 6147-99 from the Leukemia Society of America. L. G.-R. and R. R. are exchange-graduate students from the Department of Biological Sciences, Autonomous University of Nuevo Leon, Mexico, and recipients of a fellowship from the Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico.
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Abbreviations
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Bm mature B cells |
GC germinal centers |
LEA late embryogenesis abundant |
NCBI National Center for Biotechnology Information |
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Notes
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Transmitting editor: R. L. Coffman
Received 25 June 1999,
accepted 12 January 2000.
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