中华鳖部分免疫相关基因克隆及其功能研究
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摘要
中华鳖属于古老的次生水生爬行动物,作为变温羊膜腔动物向恒温动物羊膜腔进化的联结点,不仅在生命科学研究、野生资源保护等方面具有重要的科研价值；而且中华鳖具有较高的食用和药用价值,已成为我国及东南亚某些地区的主要特种水产养殖品种之一。然而,由于品种退化、病害严重以及基础研究薄弱等问题,严重影响中华鳖研究和养殖业的可持续发展。本研究通过对中华鳖免疫相关基因的克隆和功能分析,旨在探明中华鳖天然免疫应答、应激反应的机制,为深入开展中华鳖免疫学、系统发育以及病原与机体互作研究等奠定了良好的基础。
1.中华鳖tMyD88全长cDNA克隆及其组织表达差异分析
MyD88是启动先天免疫的主要接头分子之一,本试验首次获得爬行动物属的中华鳖MyD88(tMyD88)全长cDNA。经序列分析,全长tMyD88cDNA ORF为894-bp,编码297个氨基酸,N-端和C-端分别具有典型的DD结构域(death domain,DD)和保守的TIR结构域(Toll/IL-IR domain)。荧光定量RT-PCR检测中华鳖经嗜水气单胞菌(Aeromonas hydrophila)攻毒后不同脏器中(MyD88mRNA相对转录水平由高到低为,脾脏>血液>肺脏>肝脏>肾脏>小肠>心脏>肌肉。RAW2647细胞经pcDNA-tMyD88转染后,NF-κB活性显著高于对照组(673.8vs410.7,P<0.05),转染细胞上清液中IL-1p和TNF-α含量显著高于对照组(P<0.01)。结果表明,获得的中华鳖tMyD88全长cDNA分子具有与哺乳动物类似的生物学活性,可能在中华鳖抗感染免疫中具有重要的作用。
2.中华鳖热休克蛋白基因tHsc70、tGRP78和tHsp72鉴定及热应激对其表达的影响
Hsp70s (70kDa heat shock proteins)作为分子伴侣,不仅参与机体的蛋白质折叠、运输,而且可能介导机体免疫。本试验克隆和鉴定了中华鳖热休克蛋白基因tHsc70、tGRP78和tHsp72。tHsc70全长cDNA ORF为1941-bp,编码647个氨基酸,与脊椎动物Hsc70(heat shock cognate protein70)分子在核苷酸和氨基酸同源性分别在80-87.7%和95.5-99.5%；tGRP78cDNA全长ORF为1980-bp,编码660个氨基酸,与脊椎动物的GRP78(glucose regulated protein78)分子在核苷酸和氨基酸同源性分别在79.3-80.3%和92.3-94%；tHsp72全长cDNA ORF为1908-bp,编码636个氨基酸,与脊椎动物的Hsp72(inducible heat shock protein70)分子在核苷酸和氨基酸同源性分别在72-76.5%和83.6-89.1%。三个中华鳖热休克蛋白70分子均具有ATPase结合结构域、底物结合结构域、ATP/GTP结合位点基序(AEAYLGRKK)、 Hsp70s家族的三个特征性的序列标签(IDLGTTYS, IFDLGGGTFDVSIL, IVLVGGSTRIPKIQ)以及胞质(EEVD)/内质网(KDEL)一致性序列。Western-blotting分析表明,原核表达纯化的tHsc70和tHsp72个热休克蛋白可与特异性的单/多克隆抗体反应。分子进化分析表明,三个中华鳖热休克蛋白70分子与美洲鳄(Alligator mississippiensis)和禽类(Gallus gallus)在同一群内,具有较近的亲缘关系。中华鳖热激(40-C)后,与对照组(25℃)相比,四个组织中的tHsc70、 tGRP78和tHsP72的mRNA转录水平呈现不同程度的变化。中华鳖在热激1-4hrs后肝脏、心脏、肺脏和肌肉四个组织的tHsc70mRNA相对转录水平出现0.25至20.35倍不等的上升,尤其经4hrs热激的中华鳖肝脏组织上升最显著,为对照组的20.35倍(P<0.01)。4hrs应激组中华鳖肝脏中tGRP78mRNA相对转录水平与对照组相比增加最明显,约为1.86倍(P<0.05)。但肝脏中tHsP72的mRNA相对转录水平在2hrs热激后到达峰值,约为对照组的4.66倍(尸<0.05),随后出现轻微下降。Western blotting分析,中华鳖2hrs和4hrs热激以及热激1h、2hrs和4hrs结合恢复1h时肝脏中tHsc70蛋白相对表达量比对照组显著升高(P<0.05)；热激1h、2hrs和4hrs后肝脏中tGRP78蛋白相对表达比对照组均有显著升高(P<0.05)。上述结果显示,克隆的3个分子为中华鳖热休克蛋白70,具有较高的保守性；中华鳖热激后,不同组织的热休克蛋白70存在不同的表达模式,可能与细胞保护等有关。
3.病原相关模式分子对中华鳖Toll样受体及其免疫相关基因表达的影响
从中华鳖脾脏中PCR扩增出tlr2(1112bp)、tlr3(565bp)、tlr4(990bp)和il-1β(159bp)的cDNA部分序列。中华鳖TLR2测序后经序列比较和结构域分析显示,该序列与斑马鱼、鸡等脊椎动物的TLR2序列同源性和相似性分别为60.8-74.4%和58.6-76%,该片段包含富亮氨酸重复C端结构域(Leucine rich repeat C-terminal domain, LRRCT)(aa1-47),跨膜结构域(Transmembrane domain)(aa49-71)和TIR结构域(Toll-like/IL-1receptor domain)(aa101-244)。中华鳖TLR3与其他脊椎动物的TLR3序列同源性和相似性分别为58-81.2%和51.9-76.1%,包含跨膜结构域(aa10-32)和TIR结构域(aa62-188)。中华鳖TLR4与其他脊椎动物的相应分子的序列同源性和相似性分别为48.5-67.4%和38.2-63%,包含连续的3个LRR(aa23-46,47-70,71-94), LRRCT(aa107-157),跨膜结构域(aa171-193)和TIR结构域(aa206-330)。中华鳖IL-1p经BlastP分析显示其与鸡IL-1β(aa66-118)之间相似性达到60.4%,与其他脊椎动物的IL-1β序列同源性和相似性分别为49.7-61.4%和28.3-49.1%。用代表性病原相关模式分子(pathogen associated molecular pattern, PAMP)不同浓度对中华鳖外周血细胞TLRs等相关免疫分子表达影响的分析表明,中华鳖外周血细胞经4000ng/mL Zymosan刺激2hrs后tlr2mRNA的表达水平较高,il-1β mRNA的相对表达水平随着刺激浓度的提高而增加。Poly(I:C)浓度在40-8000ng/mL之间,tlr3mRNA的相对表达水平随着Poly(I:C)浓度的增加出现逐渐下降的趋势。28℃条件下,Poly(I:C)(?)低浓度(40ng/mL)和高浓度(4000ng/mL)刺激均能使tHsP72mRNA转录水平提高；LPS刺激后,tlr4、tMyD88和il-1β mRNA的相对转录水平随着浓度的提高而增加。37℃条件下,Poly(I:C)刺激组的tlr3基因表达比28℃组高1.46倍。上述结果初步表明,中华鳖Toll样受体、MyD88、Hsp70s和il-1β对部分PAMP分子刺激具有不同程度的响应性。
综上所述,本研究首次克隆和鉴别了中华鳖tMyD88, tHsc70、 tGRP78和tHsp72全长cDNA分子以及tlr2、tlr3、tlr4和il-1βcDNA部分序列,8个克隆的中华鳖分子均与禽类和爬行类的相应分子位于同一个姐妹群,而与哺乳动物、两栖类和鱼类等其他物种处于不同的亚群,中华鳖或其细胞在受到PAMP分子和／或热激后,相关基因呈现不同的表达差异变化,提示它们具有一定的生物学功能。研究结果为进一步开展基因结构与功能分析、中华鳖的天然免疫机制和系统发育等研究提供了良好的基础资料。
Chinese soft-shell turtle Pelodiscus sinensis is an ancient ectothermic amniotes reptile with an evolutionary link between ectothermic anamniotic fishes and amphibians and endothermic amniotic birds and mammals. It is not only of great importance in life science research and protection of wildlife resources, but also of edible and medicinal values. It has become one of the major farmed species in China and southeastern Asian countries. However, deterioration of the breeding stock, severe infectious diseases and lack of basic research on its biology has greatly affected the sustainability of the turtle farming industry. This dissertation covers a series of experiments for cloning and functional studies of some immune-related genes in an attempt to explore the primary mechanisms of its innate immunity and responses to heat stress and pathogen associates molecular patterns (PAMP). The results could serve as good foundations for further research in immunobiological and phylogenetic aspects of turtles as well as in host-microbe interactions.
1. Cloning and expression profiling of full-length tMyD88cDNA from Chinese soft-shelled turtle.
Myeloid differentiation factor88(MyD88) is one of the key adaptor proteins to signal transduction that triggers downstream cascades involved in innate immunity. This study identified the MyD88gene from Chinese soft-shelled turtle (tMyD88), representing the first example from reptile species. The tMyD88has an894-bp ORF and encodes a polypeptide of297amino acids including a typical death domain (DD) at the N-terminus and a conservative Toll/IL-1R (TIR) domain at the C-terminus. Its mRNA expression in organs of turtles challenged with live cells of Aeromonas hydrophila were in the order from high to low levels as spleen, blood, lungs, liver, kidneys and intestines, as determined by real-time PCR. RAW264.7macrophage cells transfected with pcDNA-tMyD88showed higher NF-κB activity than the vector control (673.8vs410.7. P<0.05). Expression of proinflammatory cytokines IL-1(3and TNF-a was also significantly higher in RAW264.7cells expressing tMyD88than the cells containing control vector (P<0.01). These results indicate that tMyD88might possess an important role in defense against microbial infection in Chinese soft-shelled turtles similar to that in mammals.
2. Identification of tHsc70, tGRP78and tHsp72in Chinese soft-shelled turtle and their expression in response to heat stress
The70kDa heat shock proteins (Hsp70s) are molecular chaperones that are not only involved in protein folding and transport, but also in initiating host immune responses. In this study, Hsp70s full-length cDNA molecules from P. sinensis were cloned and identified. The turtle Hsc70(heat shock cognate protein70. tHsc70) has a1941bp ORF encoding646amino acids and has identities to Hsc70of other vertebrates at80-87.7%(nucleotide) and95.5-99.5%(amino acid). Turtle GRP78(glucose regulated protein78, tGRP78) has an ORF of1980bp encoding660amino acids with nucleotide and amino acid identities at79.3-80.3%and92.3-94%respectively to that of other vertebrates. Turtle Hsp72(inducible heat shock protein70. tHsp72) has an ORF of1908bp coding for636amino acids and possess identities to Hscp72of other vertebrates at72-76.5%(nucleotide) and83.6-89.1%(amino acid). Two major domains for binding to ATPase (ABD) and to substrates (SBD), an ATP/GTP-binding motif (AEAYLGRKK), three signature regions characteristic of Hsp70s (IDLGTTYS, IFDLGGGTFDVSIL,1VLVGGSTRIPKIQ) and consensus plasmic(EEVD)/endoreticulum(KDEL) sequences are present in the deduced amino acids of these three molecules. The prokaryotic expression products of tHsc70and tHsp72reacted with mouse monoclonal (Hsc70) and polyclonal rabbit antibodies against human recombinant Hsp72. respectively, as shown by Western-blotting. Phylogenetically. these molecules fall into the same group to Alligator mississippiensis and Gallus gallus. There were differences of transcription of tHsc70, tGRP78and tHsp72mRNA of4tissues/organs from turtles stressed at40℃as compared to25℃. Heat stress for1to4hrs induced0.25to20.35-fold increase of tHsc70mRNA in live, hear, lung and muscles with its expression in liver significantly higher (20.35-fold, P<0.01) with4-hrs stress than control treatment at25℃. Heat stress for4hours also showed1.86-fold increase (P<0.05) in tGRP78expression as compared to the control. tHsp72showed the highest expression in liver.4.66-fold higher than control (P<0.05) at hour2after treatment and declined thereafter. Western blot analysis indicated that tHsc70expression was significantly higher (P<0.05) than the control treatment in liver of turtles heat stressed for1,2and4hrs with1-h adaptive recovery. Heat stress for1h,2hrs and4hrs induced higher expression of tGRP78in liver than the controls (P<0.05). In summary, we have successfully cloned three Hsp70family proteins from Chinese soft-shelled turtles. They are relatively conserved molecules as compared with those of other vertebrates and functional to heat stress though the expression profiles varied with tissues of turtles examined with highest response in liver.
3. Effects of representative pathogen associated molecular patterns on expression of Toll-like receptors and immune-related genes.
Partial cDNA fragments of tlr2(1112bp), tlr3(565bp), tlr4(990bp) and il-1β (159bp) were PCR-amplified and sequenced. Sequence comparison indicates that turtle TLR2has nucleotide identity of60.8-74.4%and amino acid similarity of58.6-76%to that of other vertebrates such as zebrafish and chicken. Domain analysis reveals that the deduced amino acid sequence of turtle TLR2contains a leucine rich repeat C-terminal domain, LRRCT)(aal-47), a transmembrane domain (aa49-71) and a Toll-like/IL-1receptor domain, TIR)(aa101-244). Turtle TLR3is homologous to the counterpart of other vertebrates including zebrafish and chicken between58-81.2%at the nucleotide level and51.9-76.1%at the amino acid level. It contains a transmembrane domain (aa10-32) and a TIR domain (aa62-188). The homology between turtle TLR4and those from other vertebrates is between48.5-67.4%and38.2-63%at the nucleotide and amino acid levels respectively. Deduced amino acid sequence of turtle tlr4contains three LRR (aa23-46,47-70and71-94), an LRRCT (aa107-157), a transmembrane domain (aal71-193) and a TIR domain (aa206-330). The putative turtle IL-1β has a high identity to the chicken counterpart (aa66-118)(60%at the amino acid level) and is homologous to those of other vertebrates between49.7-61.4%and28.3-49.1%at the nucleotide and amino acid levels respectively. Representative PAMPs were used to examine the response of turtle whole blood cells to stimulation. Turtle tlr2was found to have higher expression in the blood cells exposed to4000ng/ml of zymosan for2hrs. Expression of il-1β increased with increasing concentration of zymosan treatment. The mRNA expression of tlr3exhibited a tendency of decrease with increasing levels of Poly(I:C) between40-8000ng/ml). In whole blood incubated at28℃, tHsp72mRNA expression increased at both lower (40ng/ml) and higher (4000ng/ml) concentrations. mRNA expression of tlr4, tMyD88and il-1β increased with increasing concentrations. Expression of tlr3mRNA increased by1.46-fold in Poly(1:C) treated whole blood cells incubated at37℃, as compared with the same treatment but incubated at28℃. These results provide preliminary evidence that the TLRs, tMyD88, tHsp70s and il-1β in Chinese soft-shelled turtle could respond to PAMP molecules to some degree, though with varying intensity.
In summary, this study has generated for the first time the full-length cDNA sequence data of tMyD88, tHsc70, tGRP78and tHsp72as well as partial cDNA of tlr2, tlr3, tlr4and il-1β from Chinese soft-shelled turtle. These molecules are clustered with those from avian species and reptiles as the sister group, but fall into a different subgroup with those of mammals, amphibians and fish. Majority of these molecules responded to stimulation with PAMPs or heat stress and the degree and profile of the responses vary with stimuli or their concentration, indicating that they possess biological functions similar to those from other vertebrates. Findings in the present study may provide good foundation for further research into the structure-function relationship of these molecules, mechanisms of innate immunity in turtles and its role from the evolutionary perspective.
1.中华鳖tMyD88全长cDNA克隆及其组织表达差异分析
MyD88是启动先天免疫的主要接头分子之一,本试验首次获得爬行动物属的中华鳖MyD88(tMyD88)全长cDNA。经序列分析,全长tMyD88cDNA ORF为894-bp,编码297个氨基酸,N-端和C-端分别具有典型的DD结构域(death domain,DD)和保守的TIR结构域(Toll/IL-IR domain)。荧光定量RT-PCR检测中华鳖经嗜水气单胞菌(Aeromonas hydrophila)攻毒后不同脏器中(MyD88mRNA相对转录水平由高到低为,脾脏>血液>肺脏>肝脏>肾脏>小肠>心脏>肌肉。RAW2647细胞经pcDNA-tMyD88转染后,NF-κB活性显著高于对照组(673.8vs410.7,P<0.05),转染细胞上清液中IL-1p和TNF-α含量显著高于对照组(P<0.01)。结果表明,获得的中华鳖tMyD88全长cDNA分子具有与哺乳动物类似的生物学活性,可能在中华鳖抗感染免疫中具有重要的作用。
2.中华鳖热休克蛋白基因tHsc70、tGRP78和tHsp72鉴定及热应激对其表达的影响
Hsp70s (70kDa heat shock proteins)作为分子伴侣,不仅参与机体的蛋白质折叠、运输,而且可能介导机体免疫。本试验克隆和鉴定了中华鳖热休克蛋白基因tHsc70、tGRP78和tHsp72。tHsc70全长cDNA ORF为1941-bp,编码647个氨基酸,与脊椎动物Hsc70(heat shock cognate protein70)分子在核苷酸和氨基酸同源性分别在80-87.7%和95.5-99.5%；tGRP78cDNA全长ORF为1980-bp,编码660个氨基酸,与脊椎动物的GRP78(glucose regulated protein78)分子在核苷酸和氨基酸同源性分别在79.3-80.3%和92.3-94%；tHsp72全长cDNA ORF为1908-bp,编码636个氨基酸,与脊椎动物的Hsp72(inducible heat shock protein70)分子在核苷酸和氨基酸同源性分别在72-76.5%和83.6-89.1%。三个中华鳖热休克蛋白70分子均具有ATPase结合结构域、底物结合结构域、ATP/GTP结合位点基序(AEAYLGRKK)、 Hsp70s家族的三个特征性的序列标签(IDLGTTYS, IFDLGGGTFDVSIL, IVLVGGSTRIPKIQ)以及胞质(EEVD)/内质网(KDEL)一致性序列。Western-blotting分析表明,原核表达纯化的tHsc70和tHsp72个热休克蛋白可与特异性的单/多克隆抗体反应。分子进化分析表明,三个中华鳖热休克蛋白70分子与美洲鳄(Alligator mississippiensis)和禽类(Gallus gallus)在同一群内,具有较近的亲缘关系。中华鳖热激(40-C)后,与对照组(25℃)相比,四个组织中的tHsc70、 tGRP78和tHsP72的mRNA转录水平呈现不同程度的变化。中华鳖在热激1-4hrs后肝脏、心脏、肺脏和肌肉四个组织的tHsc70mRNA相对转录水平出现0.25至20.35倍不等的上升,尤其经4hrs热激的中华鳖肝脏组织上升最显著,为对照组的20.35倍(P<0.01)。4hrs应激组中华鳖肝脏中tGRP78mRNA相对转录水平与对照组相比增加最明显,约为1.86倍(P<0.05)。但肝脏中tHsP72的mRNA相对转录水平在2hrs热激后到达峰值,约为对照组的4.66倍(尸<0.05),随后出现轻微下降。Western blotting分析,中华鳖2hrs和4hrs热激以及热激1h、2hrs和4hrs结合恢复1h时肝脏中tHsc70蛋白相对表达量比对照组显著升高(P<0.05)；热激1h、2hrs和4hrs后肝脏中tGRP78蛋白相对表达比对照组均有显著升高(P<0.05)。上述结果显示,克隆的3个分子为中华鳖热休克蛋白70,具有较高的保守性；中华鳖热激后,不同组织的热休克蛋白70存在不同的表达模式,可能与细胞保护等有关。
3.病原相关模式分子对中华鳖Toll样受体及其免疫相关基因表达的影响
从中华鳖脾脏中PCR扩增出tlr2(1112bp)、tlr3(565bp)、tlr4(990bp)和il-1β(159bp)的cDNA部分序列。中华鳖TLR2测序后经序列比较和结构域分析显示,该序列与斑马鱼、鸡等脊椎动物的TLR2序列同源性和相似性分别为60.8-74.4%和58.6-76%,该片段包含富亮氨酸重复C端结构域(Leucine rich repeat C-terminal domain, LRRCT)(aa1-47),跨膜结构域(Transmembrane domain)(aa49-71)和TIR结构域(Toll-like/IL-1receptor domain)(aa101-244)。中华鳖TLR3与其他脊椎动物的TLR3序列同源性和相似性分别为58-81.2%和51.9-76.1%,包含跨膜结构域(aa10-32)和TIR结构域(aa62-188)。中华鳖TLR4与其他脊椎动物的相应分子的序列同源性和相似性分别为48.5-67.4%和38.2-63%,包含连续的3个LRR(aa23-46,47-70,71-94), LRRCT(aa107-157),跨膜结构域(aa171-193)和TIR结构域(aa206-330)。中华鳖IL-1p经BlastP分析显示其与鸡IL-1β(aa66-118)之间相似性达到60.4%,与其他脊椎动物的IL-1β序列同源性和相似性分别为49.7-61.4%和28.3-49.1%。用代表性病原相关模式分子(pathogen associated molecular pattern, PAMP)不同浓度对中华鳖外周血细胞TLRs等相关免疫分子表达影响的分析表明,中华鳖外周血细胞经4000ng/mL Zymosan刺激2hrs后tlr2mRNA的表达水平较高,il-1β mRNA的相对表达水平随着刺激浓度的提高而增加。Poly(I:C)浓度在40-8000ng/mL之间,tlr3mRNA的相对表达水平随着Poly(I:C)浓度的增加出现逐渐下降的趋势。28℃条件下,Poly(I:C)(?)低浓度(40ng/mL)和高浓度(4000ng/mL)刺激均能使tHsP72mRNA转录水平提高；LPS刺激后,tlr4、tMyD88和il-1β mRNA的相对转录水平随着浓度的提高而增加。37℃条件下,Poly(I:C)刺激组的tlr3基因表达比28℃组高1.46倍。上述结果初步表明,中华鳖Toll样受体、MyD88、Hsp70s和il-1β对部分PAMP分子刺激具有不同程度的响应性。
综上所述,本研究首次克隆和鉴别了中华鳖tMyD88, tHsc70、 tGRP78和tHsp72全长cDNA分子以及tlr2、tlr3、tlr4和il-1βcDNA部分序列,8个克隆的中华鳖分子均与禽类和爬行类的相应分子位于同一个姐妹群,而与哺乳动物、两栖类和鱼类等其他物种处于不同的亚群,中华鳖或其细胞在受到PAMP分子和／或热激后,相关基因呈现不同的表达差异变化,提示它们具有一定的生物学功能。研究结果为进一步开展基因结构与功能分析、中华鳖的天然免疫机制和系统发育等研究提供了良好的基础资料。
Chinese soft-shell turtle Pelodiscus sinensis is an ancient ectothermic amniotes reptile with an evolutionary link between ectothermic anamniotic fishes and amphibians and endothermic amniotic birds and mammals. It is not only of great importance in life science research and protection of wildlife resources, but also of edible and medicinal values. It has become one of the major farmed species in China and southeastern Asian countries. However, deterioration of the breeding stock, severe infectious diseases and lack of basic research on its biology has greatly affected the sustainability of the turtle farming industry. This dissertation covers a series of experiments for cloning and functional studies of some immune-related genes in an attempt to explore the primary mechanisms of its innate immunity and responses to heat stress and pathogen associates molecular patterns (PAMP). The results could serve as good foundations for further research in immunobiological and phylogenetic aspects of turtles as well as in host-microbe interactions.
1. Cloning and expression profiling of full-length tMyD88cDNA from Chinese soft-shelled turtle.
Myeloid differentiation factor88(MyD88) is one of the key adaptor proteins to signal transduction that triggers downstream cascades involved in innate immunity. This study identified the MyD88gene from Chinese soft-shelled turtle (tMyD88), representing the first example from reptile species. The tMyD88has an894-bp ORF and encodes a polypeptide of297amino acids including a typical death domain (DD) at the N-terminus and a conservative Toll/IL-1R (TIR) domain at the C-terminus. Its mRNA expression in organs of turtles challenged with live cells of Aeromonas hydrophila were in the order from high to low levels as spleen, blood, lungs, liver, kidneys and intestines, as determined by real-time PCR. RAW264.7macrophage cells transfected with pcDNA-tMyD88showed higher NF-κB activity than the vector control (673.8vs410.7. P<0.05). Expression of proinflammatory cytokines IL-1(3and TNF-a was also significantly higher in RAW264.7cells expressing tMyD88than the cells containing control vector (P<0.01). These results indicate that tMyD88might possess an important role in defense against microbial infection in Chinese soft-shelled turtles similar to that in mammals.
2. Identification of tHsc70, tGRP78and tHsp72in Chinese soft-shelled turtle and their expression in response to heat stress
The70kDa heat shock proteins (Hsp70s) are molecular chaperones that are not only involved in protein folding and transport, but also in initiating host immune responses. In this study, Hsp70s full-length cDNA molecules from P. sinensis were cloned and identified. The turtle Hsc70(heat shock cognate protein70. tHsc70) has a1941bp ORF encoding646amino acids and has identities to Hsc70of other vertebrates at80-87.7%(nucleotide) and95.5-99.5%(amino acid). Turtle GRP78(glucose regulated protein78, tGRP78) has an ORF of1980bp encoding660amino acids with nucleotide and amino acid identities at79.3-80.3%and92.3-94%respectively to that of other vertebrates. Turtle Hsp72(inducible heat shock protein70. tHsp72) has an ORF of1908bp coding for636amino acids and possess identities to Hscp72of other vertebrates at72-76.5%(nucleotide) and83.6-89.1%(amino acid). Two major domains for binding to ATPase (ABD) and to substrates (SBD), an ATP/GTP-binding motif (AEAYLGRKK), three signature regions characteristic of Hsp70s (IDLGTTYS, IFDLGGGTFDVSIL,1VLVGGSTRIPKIQ) and consensus plasmic(EEVD)/endoreticulum(KDEL) sequences are present in the deduced amino acids of these three molecules. The prokaryotic expression products of tHsc70and tHsp72reacted with mouse monoclonal (Hsc70) and polyclonal rabbit antibodies against human recombinant Hsp72. respectively, as shown by Western-blotting. Phylogenetically. these molecules fall into the same group to Alligator mississippiensis and Gallus gallus. There were differences of transcription of tHsc70, tGRP78and tHsp72mRNA of4tissues/organs from turtles stressed at40℃as compared to25℃. Heat stress for1to4hrs induced0.25to20.35-fold increase of tHsc70mRNA in live, hear, lung and muscles with its expression in liver significantly higher (20.35-fold, P<0.01) with4-hrs stress than control treatment at25℃. Heat stress for4hours also showed1.86-fold increase (P<0.05) in tGRP78expression as compared to the control. tHsp72showed the highest expression in liver.4.66-fold higher than control (P<0.05) at hour2after treatment and declined thereafter. Western blot analysis indicated that tHsc70expression was significantly higher (P<0.05) than the control treatment in liver of turtles heat stressed for1,2and4hrs with1-h adaptive recovery. Heat stress for1h,2hrs and4hrs induced higher expression of tGRP78in liver than the controls (P<0.05). In summary, we have successfully cloned three Hsp70family proteins from Chinese soft-shelled turtles. They are relatively conserved molecules as compared with those of other vertebrates and functional to heat stress though the expression profiles varied with tissues of turtles examined with highest response in liver.
3. Effects of representative pathogen associated molecular patterns on expression of Toll-like receptors and immune-related genes.
Partial cDNA fragments of tlr2(1112bp), tlr3(565bp), tlr4(990bp) and il-1β (159bp) were PCR-amplified and sequenced. Sequence comparison indicates that turtle TLR2has nucleotide identity of60.8-74.4%and amino acid similarity of58.6-76%to that of other vertebrates such as zebrafish and chicken. Domain analysis reveals that the deduced amino acid sequence of turtle TLR2contains a leucine rich repeat C-terminal domain, LRRCT)(aal-47), a transmembrane domain (aa49-71) and a Toll-like/IL-1receptor domain, TIR)(aa101-244). Turtle TLR3is homologous to the counterpart of other vertebrates including zebrafish and chicken between58-81.2%at the nucleotide level and51.9-76.1%at the amino acid level. It contains a transmembrane domain (aa10-32) and a TIR domain (aa62-188). The homology between turtle TLR4and those from other vertebrates is between48.5-67.4%and38.2-63%at the nucleotide and amino acid levels respectively. Deduced amino acid sequence of turtle tlr4contains three LRR (aa23-46,47-70and71-94), an LRRCT (aa107-157), a transmembrane domain (aal71-193) and a TIR domain (aa206-330). The putative turtle IL-1β has a high identity to the chicken counterpart (aa66-118)(60%at the amino acid level) and is homologous to those of other vertebrates between49.7-61.4%and28.3-49.1%at the nucleotide and amino acid levels respectively. Representative PAMPs were used to examine the response of turtle whole blood cells to stimulation. Turtle tlr2was found to have higher expression in the blood cells exposed to4000ng/ml of zymosan for2hrs. Expression of il-1β increased with increasing concentration of zymosan treatment. The mRNA expression of tlr3exhibited a tendency of decrease with increasing levels of Poly(I:C) between40-8000ng/ml). In whole blood incubated at28℃, tHsp72mRNA expression increased at both lower (40ng/ml) and higher (4000ng/ml) concentrations. mRNA expression of tlr4, tMyD88and il-1β increased with increasing concentrations. Expression of tlr3mRNA increased by1.46-fold in Poly(1:C) treated whole blood cells incubated at37℃, as compared with the same treatment but incubated at28℃. These results provide preliminary evidence that the TLRs, tMyD88, tHsp70s and il-1β in Chinese soft-shelled turtle could respond to PAMP molecules to some degree, though with varying intensity.
In summary, this study has generated for the first time the full-length cDNA sequence data of tMyD88, tHsc70, tGRP78and tHsp72as well as partial cDNA of tlr2, tlr3, tlr4and il-1β from Chinese soft-shelled turtle. These molecules are clustered with those from avian species and reptiles as the sister group, but fall into a different subgroup with those of mammals, amphibians and fish. Majority of these molecules responded to stimulation with PAMPs or heat stress and the degree and profile of the responses vary with stimuli or their concentration, indicating that they possess biological functions similar to those from other vertebrates. Findings in the present study may provide good foundation for further research into the structure-function relationship of these molecules, mechanisms of innate immunity in turtles and its role from the evolutionary perspective.
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