更新于：2024-09-19

SLC38A2

更新于：2024-09-19

基本信息

别名

Amino acid transporter A2、ATA2、KIAA1382

+ [10]

简介

Symporter that cotransports neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane (PubMed:10930503, PubMed:15922329, PubMed:16621798, PubMed:15774260). The trasnport is pH-sensitive, Li(+)-intolerant, electrogenic, driven by the Na(+) electrochemical gradient and cotransports of neutral amino acids and sodium ions with a stoichiometry of 1:1. May function in the transport of amino acids at the blood-brain barrier (PubMed:10930503, PubMed:15774260). May function in the transport of amino acids in the supply of maternal nutrients to the fetus through the placenta (By similarity). Maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate (By similarity). Transports L-proline in differentiating osteoblasts for the efficient synthesis of proline-enriched proteins and provides proline essential for osteoblast differentiation and bone formation during bone development (By similarity).

关联

100 项与 SLC38A2 相关的临床结果

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100 项与 SLC38A2 相关的转化医学

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0 项与 SLC38A2 相关的专利（医药）

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417

项与 SLC38A2 相关的文献（医药）

2024-12-01·Molecular Biology Reports

Bacterial over-production of the functionally active human SLC38A2 (SNAT2) exploiting the mistic tag: a cheap and fast tool for testing ligands

Article

作者: Indiveri, Cesare ; Tripicchio, Martina ; Console, Lara ; Galluccio, Michele

AbstractBackgroundSLC38A2 is a ubiquitously expressed Na+-dependent transporter specific for small and medium neutral amino acids. It is involved in human pathologies, such as type II diabetes and cancer. Despite its relevance in human physio-pathology, structure/function relationship studies and identification of ligands with regulatory roles are still in infancy.Methods and ResultsThe cDNA coding for SLC38A2 was cloned in the pET-28-Mistic vector, and the BL21 codon plus RIL strain was transformed with the recombinant construct. 0.5% glucose and oxygen availability were crucial for protein expression. The over-expressed hSNAT2-Mistic chimera was cleaved on column and purified by nickel-chelating affinity chromatography, with a yield of about 60 mg/Liter cell culture. The purified hSNAT2 was reconstituted in proteoliposomes in an active form with a right-side-out orientation with respect to the native membrane.ConclusionsThe addition of a Mistic tag at the N-terminus of the SNAT2 protein was crucial for its over-expression and purification. The purified protein was functionally active, representing a powerful tool for performing structure/function studies and testing ligands as inhibitors and/or activators.

2024-07-15·The FASEB Journal

Sex‐specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

Article

作者: Muller Oliveira Nascimento, Veronica ; Pereira‐Carvalho, Daniela ; Barbosa Dias, Wagner ; Silva Alves, Rakel Kelly ; Gomes Medeiros, Inácio ; Fontes Dias, Ariane ; Ortiga‐Carvalho, Tania Maria ; Regina Todeschini, Adriane ; Lopes Brum, Felipe ; Borba Vieira Andrade, Cherley ; Bloise, Enrrico ; Chagas Valim, Alessandra Cristina ; Barros Arruda, Luciana ; Antunes Coelho, Sharton Vinicius ; dos Santos, Ronan Christian

AbstractMaternal Zika virus (ZIKV) infection during pregnancy has been associated with severe intrauterine growth restriction (IUGR), placental damage, metabolism disturbances, and newborn neurological abnormalities. Here, we investigated the impact of maternal ZIKV infection on placental nutrient transporters and nutrient‐sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU‐ZIKVPE243) or High (5 × 107 PFU‐ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, and tissue was collected at GD18.5 (term). Fetal–placental growth was impaired in male fetuses, which exhibited higher placental expression of the ZIKV infective marker, eukaryotic translation initiation factor 2 (eIF2α), but lower levels of phospho‐eIF2α. There were no differences in fetal–placental growth in female fetuses, which exhibited no significant alterations in placental ZIKV infective markers. Furthermore, ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose‐6‐phosphate in female placentae, with no differences in amino acid transport potential. In contrast, ZIKV did not impact glucose transporters in male placentae but downregulated sodium‐coupled neutral amino acid 2 (Snat2) transporter expression. We also observed sex‐dependent differences in the hexosamine biosynthesis pathway (HBP) and O‐GlcNAcylation in ZIKV‐infected pregnancies, showing that ZIKV can disturb placental nutrient sensing. Our findings highlight molecular alterations in the placenta caused by maternal ZIKV infection, shedding light on nutrient transport, sensing, and availability. Our results also suggest that female and male placentae employ distinct coping mechanisms in response to ZIKV‐induced metabolic changes, providing insights into therapeutic approaches for congenital Zika syndrome.

2024-07-01·Plant Physiology and Biochemistry

Melatonin mediated tolerance to benzalkonium chloride phytotoxicity through improved growth, photochemical reactions, and antioxidant system in wild-type and snat2 mutant Arabidopsis lines

Article

作者: Turkan, Ismail ; Yildiztugay, Evren ; Arikan Abdulveli, Busra ; Ozfidan-Konakci, Ceyda

Melatonin (Mel) is a phytohormone that plays a crucial role in various plant processes, including stress response. Despite numerous studies on the role of Mel in stress resistance, its significance in plants exposed to benzalkonium chloride (BAC) pollution remains unexplored. BAC, a common antiseptic, poses a threat to terrestrial plants due to its widespread use and inefficient removal, leading to elevated concentrations in the environment. This study investigated the impact of BAC (0.5 mg L^-1) pollution on wild-type Col-0 and snat2 knockout mutant Arabidopsis lines, revealing reduced growth, altered water relations, and gas exchange parameters. On the other hand, exogenous Mel (100 μM) treatments mitigated BAC-induced phytotoxicity and increased the growth rate by 1.8-fold in Col-0 and 2-fold in snat2 plants. snat2 mutant seedlings had a suppressed carbon assimilation rate (A) under normal conditions, but BAC contamination led to further A repression by 71% and 48% in Col-0 and snat2 leaves, respectively. However, Mel treatment on stressed plants was successful in improving F_v/F_m and increased the total photosynthesis efficiency by regulating photochemical reactions. Excessive H₂O₂ accumulation in the guard cells of plants exposed to BAC pollution was detected by confocal microscopy. Mel treatments triggered almost all antioxidant enzyme activities (except POX) in both Arabidopsis lines under stress. This enhanced antioxidant activity, facilitated by foliar Mel application, contributed to the alleviation of oxidative damage, regulation of photosynthesis reactions, and promotion of plant growth in Arabidopsis. In addition to corroborating results observed in many agricultural plants regarding the development of tolerance to environmental stresses, this study provides novel insights into the action mechanisms of Mel under the emerging pollutant benzalkonium chloride.

项与 SLC38A2 相关的新闻（医药）

2023-07-10

·药明康德

前沿 | 补充这种氨基酸，能让免疫细胞打赢癌细胞！《自然》新研究揭示抗癌的关键营养素

▎药明康德内容团队编辑免疫疗法的发展为癌症治疗带来了巨大飞跃，其基本思路是通过激发患者自身免疫系统的力量对抗肿瘤。例如，免疫检查点阻断疗法通过阻断癌细胞发送给免疫细胞的“刹车”信号，解除肿瘤微环境对免疫细胞的抑制。不过，免疫检查点阻断疗法目前还只能让一部分患者受益，因此很多研究者正在寻找增强免疫疗法抗癌活性的新方法。日前，美国圣裘德儿童研究医院（St. Jude Children's Research Hospital）迟洪波课题组在《自然》杂志上刊发最新研究，揭示了癌细胞与免疫细胞争夺的一种关键营养素——谷氨酰胺（glutamine）。研究结果表明，直接向肿瘤提供谷氨酰胺，可帮助免疫系统提高抗癌活性，与免疫检查点阻断疗法相结合时显著遏制肿瘤生长。为了生存，肿瘤在汲取营养方面可谓非常贪婪。在肿瘤微环境中，癌细胞和免疫细胞需要争夺营养。谷氨酰胺就是微环境中的一种主要营养素。当谷氨酰胺不幸被癌细胞垄断，一种名为树突状细胞（dendritic cell）的免疫细胞就会“饿肚子”。树突状细胞作为高效的抗原呈递细胞，是激活抗癌T细胞的重要助手。而树突状细胞缺乏谷氨酰胺时，抗肿瘤免疫功能就会大打折扣。图片来源：123RFT细胞具有直接的癌细胞杀伤活性，常被看作肿瘤免疫疗法中的主角。然而，它们并不能靠单打独斗就对付癌细胞，在这项新研究中，科学家们强调了激活T细胞的树突状细胞在肿瘤微环境中的角色。迟洪波教授在圣裘德儿童研究医院的新闻稿中打了一个容易理解的比方：“我们可以将树突状细胞视为驾驶员，将T细胞视为汽车。如果没有司机，汽车无法移动。此外，谷氨酰胺等营养素相当于司机的驾照。”在肿瘤小鼠中，研究人员通过直接注射的方式向瘤内补充谷氨酰胺后，观察到小鼠的肿瘤生长得到抑制。不仅如此，补充谷氨酰胺还可以提高免疫检查点抑制剂或过继性T细胞疗法的效果。▲瘤内补充谷氨酰胺可促进cDC1介导的抗肿瘤免疫（图片来源：参考资料[1]）此外，研究人员还确定了一种分子途径，可以作为潜在的药物靶点来达到给树突状细胞补充谷氨酰胺的效果。他们发现，有两种蛋白质，FLCN和SLC38A2，是树突状细胞感知并摄取谷氨酰胺所必需的，如果免疫细胞缺少这两种蛋白，在补充谷氨酰胺的情况下也不能有效激活T细胞。这些结果提示，它们或可作为药物靶点用于提升癌症疗法的效果。“除了加强治疗干预外，我们通过展示营养素如何介导细胞之间的通讯还提供了先进的概念，这是在免疫代谢领域尚且研究不足的一个概念。”迟洪波教授指出。参考资料：[1] Chuansheng Guo et al., (2023) SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature Doi: https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-023-06299-8[2] Immune and tumor cell “tug-of-war” controls anti-cancer activity. Retrieved July 6, 2023 from https://www.eurekalert.org/news-releases/994641本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

免疫疗法细胞疗法

2023-07-09

·生物谷

《自然》：肿瘤的代谢检查点太猛了！华人科学家发现，癌细胞还能通过谷氨酰胺代谢拿下T细胞的眼线

在这项研究中，迟洪波团队揭示，通过提高肿瘤微环境中的谷氨酰胺水平，可以增强树突状细胞的抗原呈递和激活T细胞的能力。肿瘤微环境，是属于肿瘤细胞和免疫细胞的战场。在这里，各类免疫细胞联手与癌细胞斗智斗勇，识别并杀伤表达异常抗原的癌细胞。而为了生存，狡诈的癌细胞也总能变着花样搞些阳谋阴谋，给肿瘤免疫治疗制造麻烦，比如开启“隐身”模式，降低其特异性抗原的表达，以及利用免疫检查点分子抑制免疫细胞活性；再或者，干脆去抢掠“粮草”——葡萄糖或氨基酸，导致细胞毒性T细胞的抗肿瘤效应功能异常等。今天这一集，咱们讲的便是营养争夺战。不过，此次战斗并非围绕抗肿瘤战役中的主角T细胞展开，而是负责唤醒T细胞的树突状细胞（DCs）。美国圣裘德儿童研究医院的迟洪波团队发现，肿瘤细胞与I型经典树突状细胞（cDC1s）会共同争夺肿瘤微环境中的谷氨酰胺。由于处于失利的一方，cDC1s细胞缺乏谷氨酰胺，这导致其抗原提呈能力减弱，无法有效激活抗肿瘤T细胞。提高肿瘤中谷氨酰胺水平，可以增强由cDC1s细胞介导的抗肿瘤免疫反应，增强免疫治疗疗效[1]。论文于近日发表在《自然》期刊上。按照迟洪波教授的话来说，“这是肿瘤细胞和免疫细胞之间的一场营养拉锯战”[2]！论文首页截图树突状细胞（DCs）是抗肿瘤免疫战斗中不可缺少的一员。DCs不仅能够摄取、加工处理和呈递肿瘤相关抗原，从而激活T细胞产生针对肿瘤的免疫应答，还能够分泌细胞因子来调节更多种类免疫细胞的活性，进一步促进免疫系统对肿瘤的防御和清除。 DCs分为cDC1和cDC2两个亚群，分别负责CD8+细胞毒性T细胞、CD4+T细胞的激活。其中，能够启动细胞毒性T细胞的cDC1亚群，已被证明在癌症免疫检查点阻断治疗（ICB）和过继性T细胞疗法（ACT）的成功中发挥关键作用。然而，肿瘤微环境中的营养物质分配失衡、细胞内代谢过程发生转变会给DC的功能及其介导的抗肿瘤免疫效应带来哪些影响，尚不明确。在这项研究中，迟洪波团队先是利用结直肠癌小鼠模型（MC38）和黑色素瘤小鼠模型（B16-OVA）的样本进行代谢组学分析发现，相比于血液，肿瘤微环境中的谷氨酰胺等营养物质减少。通过每日直接注射来补充小鼠肿瘤内的谷氨酰胺水平后观察到，小鼠的肿瘤生长得到抑制、抗肿瘤免疫增强。此外，谷氨酰胺补充还可以提高免疫检查点阻断治疗或过继性T细胞疗法的疗效，并诱导强烈的免疫记忆。给肿瘤补充谷氨酰胺后，抗肿瘤免疫增强随后，对肿瘤微环境中的免疫细胞进行分析，研究者们发现，补充谷氨酰胺提高了肿瘤内成熟cDC1s的抗原加工处理和递呈能力，但不影响未成熟的DC细胞从外周组织向淋巴组织的迁移能力；与此同时，肿瘤内具有杀伤作用的CD8+T细胞数量增加，T细胞抗肿瘤活性增强。cDC2s等其它免疫细胞则不怎么受谷氨酰胺水平变动的影响。而且，对于缺乏cDC1s的结直肠癌或黑色素瘤小鼠来说，补充谷氨酰胺无法再显著抑制肿瘤生长。也就是说，肿瘤微环境中谷氨酰胺水平升高的受益者正是cDC1s细胞，补充谷氨酰胺通过促进cDC1s介导的抗肿瘤免疫来抑制肿瘤发展。补充谷氨酰胺的抗肿瘤效果依赖于cDC1s的存在进一步研究结果显示，相较于其它细胞，肿瘤细胞和cDC1s细胞都高表达谷氨酰胺转运蛋白SLC38A2，这种蛋白能够帮助细胞摄取和代谢谷氨酰胺。于是，肿瘤细胞与cDC1s细胞之间展开了激烈的谷氨酰胺争夺战。然而，这场战斗中似乎是肿瘤细胞更胜一筹，其表达的SLC38A2水平更高。由于肿瘤细胞的“抢食”，肿瘤微环境中的cDC1s细胞无法获取足够的谷氨酰胺，导致成熟和功能受损。利用遗传学技术使肿瘤细胞中编码SLC38A2蛋白的基因缺失，可以帮助cDC1s细胞挽回局势，显著抑制小鼠的肿瘤生长，增加肿瘤内的CD8+T细胞数量和效应功能。相反，如果是cDC1s细胞的SLC38A2蛋白表达缺失、无法正常摄取谷氨酰胺，虽然cDC1s摄取抗原的能力不受影响，但却无法再有效行使其抗原提呈的职责。此时，cDC1s细胞上负责激活T细胞的分子（如MHCI、IL-12p40）水平降低，导致小鼠肿瘤微环境中CD8+T细胞的数量减少，IFN-γ和颗粒酶B等效应分子水平降低。 cDC1s需要SLC38A2蛋白来正常吃饭不仅如此，研究者们还在cDC1s细胞中找到了与谷氨酰胺代谢紧密相关的另一个分子，即FLCN蛋白。没了FLCN蛋白，即使向cDC1细胞提供大量的谷氨酰胺，也无法提升其抗原提呈和激活T细胞的能力。另外，也揭示了cDC1s细胞中由FLCN介导的相关信号通路。谷氨酰胺调控cDC1s细胞的分子机制值得注意的是，2019年时，一篇发表在《科学》期刊上的重磅研究便以谷氨酰胺作为肿瘤代谢检查点，开创性地研发了一种小分子靶向抑制剂。这种药物通过阻断谷氨酰胺代谢来解除肿瘤微环境的免疫抑制能力，甚至能够重编程T细胞的代谢方式、直接激活T细胞[3]。但是，后续又有研究提出，尽管谷氨酰胺酶抑制可以抑制肿瘤生长，但也会损害CD8+T细胞的活化和抗肿瘤能力[4]。这些结果表明，在肿瘤微环境中，谷氨酰胺代谢对于免疫应答的调控是复杂的，存在一定的平衡关系。在这项研究中，迟洪波团队揭示，通过提高肿瘤微环境中的谷氨酰胺水平，可以增强树突状细胞的抗原呈递和激活T细胞的能力。借用迟洪波教授的形容[2]，“我们可以将树突状细胞视为驾驶员，将T细胞视为汽车。如果没有司机，汽车就不会启动。而谷氨酰胺等营养物质，可以视为驾驶员的执照。”这很形象，在缺乏谷氨酰胺的情况下，cDC1s细胞是能看见肿瘤细胞，可就是开不了车、还不了手啊！参考文献： [1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-023-06299-8 [2]https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/immune-and-tumor-cell-tug-of-war-controls-anti-cancer-activity.html [3]Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019). [4]Best, S. A. et al. Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer. Cell Metab. 34, 874–887 (2022).

免疫疗法细胞疗法

2023-07-05

·Science Daily

Immune and tumor cell 'tug-of-war' controls anti-cancer activity

Scientists have found that altering amounts of the nutrient glutamine in the tumor microenvironment could enhance or impair the immune system's anti-cancer response. Scientists at St. Jude Children's Research Hospital found immune and tumor cells compete over glutamine, a major nutrient in their local environment, with significant implications for anti-cancer activity. If cancer cells monopolize glutamine, they can prevent immune cells from destroying cancer. The findings show that supplying glutamine directly to tumors helps initiate the immune system's cancer-killing activity. The researchers also identified a molecular pathway that could serve as a potential drug target to achieve the same effect. The findings were published today in Nature. "It's a nutrient tug-of-war between tumor cells and immune cells," said corresponding author Hongbo Chi, Ph.D., St. Jude Department of Immunology. "If tumor cells use all the available glutamine, then a specialized immune cell type known as the dendritic cell is starved of glutamine, leading to impaired anti-tumor immune function. But if we can supplement enough glutamine to the tumor microenvironment, that will inhibit tumor growth because dendritic cells will use it and activate the adaptive immune response." Dendritic cells turn on cancer-killing immune cells called T cells. The group showed that resupplying glutamine in the tumor microenvironment severely reduced tumor growth because dendritic cells were then better able to activate anti-cancer T cells. The tumor microenvironment is composed of chemicals and cells around cancer cells. Infamously, cancer cells secrete many signals to turn the immune response "off" in this area, especially the T cells that threaten their destruction. The St. Jude team is the first to identify a nutrient as a major signal between cancer cells and dendritic cells in this local environment. Improving anti-cancer therapies "We are very excited to establish the link between glutamine, therapeutic effect and dendritic cells," said first author Chuansheng Guo, Ph.D., St. Jude Department of Immunology. "It's critical for the efficacy of immune checkpoint blockade and adoptive cell transfer therapy." Immune checkpoint blockade therapy inhibits the "off" signals cancer cells send to immune cells that suppress the immune response in the tumor microenvironment. These therapies have been highly effective, but only in a small number of patients. The researchers found that supplying glutamine in combination with checkpoint therapy enhanced anti-cancer activity in mice. "This paper provides a proof of concept that nutrients could act synergistically with checkpoint inhibitors for tumor treatment as a new strategy for combination therapy," Chi said. The mechanism of helping or hindering cancer-killing While much cancer research has focused on T cells because of their direct cancer-killing activity, this study is one of the first to examine how the tumor microenvironment affects the dendritic cells, which activate T cells. The researchers found that without glutamine, dendritic cells failed to activate the T cells that directly kill cancer cells. "Even though T cells are the cornerstone for anti-cancer immunity, they cannot do the job by themselves," Chi explained. "We can think of dendritic cells as the driver and the T cell as the car. If you do not have a driver, the car will not move. Moreover, nutrients like glutamine serve as the license for the driver." Similarly, when the researchers removed the proteins that respond to or take up glutamine in dendritic cells, the immune cells failed to activate cancer-killing cells. These proteins, called FLCN and SLC38A2, are important in sensing and acquiring nutrients but have not previously been connected to immune cells' reactions to tumors. They may serve as potent drug targets to improve cancer therapy. "We're extremely excited about these findings," Chi said. "In addition to enhancing the therapeutic intervention, we have provided a conceptual advance by showing how nutrients mediate cell-cell communication, an understudied concept in the field of immunometabolism." The study's other authors are Zhiyuan You, Hao Shi, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, of St. Jude, and Yu Sun and Xingrong Du, formerly of St. Jude. The study was supported by grants from the National Institutes of Health (AI105887, AI131703, AI140761, AI150241, AI150514 and CA253188) and ALSAC, the fundraising and awareness organization of St. Jude.

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