小柯机器人

SLC19A1蛋白负责转运环二核苷酸
2019-09-12 15:43

美国加州大学伯克利分校David H. Raulet课题组,发现SLC19A1蛋白负责转运免疫反应性的环二核苷酸。2019年9月11日,《自然》在线发表了这一成果。

研究人员使用全基因组CRISPR筛选鉴定到还原叶酸载体SLC19A1(一种叶酸-有机磷酸盐反向转运蛋白),作为CDN的主要转运蛋白。在人类细胞中敲除SLC19A1抑制CDN摄取和功能反应,并且过表达SLC19A1增加摄取和功能反应。在离体的人细胞系和原代细胞中,CDN摄取受到叶酸以及两种批准用于治疗炎性疾病的药物(柳氮磺胺吡啶和抗叶酸的甲氨蝶呤)的抑制。SLC19A1作为CDN进入细胞的主要转运蛋白的鉴定,对于癌症的免疫治疗、宿主对产生CDN的病原微生物的响应以及潜在的某些炎性疾病都有影响。

据介绍,细胞质中DNA的积累是与感染、癌症和基因组损伤相关的关键免疫刺激信号。细胞溶质DNA通过激活STING(cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes)通路来触发免疫应答。DNA与cGAS的结合激活其酶活性,导致第二信使——2'3'-cGAMP(cyclic guanosine monophosphate–adenosine monophosphate)的合成。这种环二核苷酸(CDN)激活STING8,STING8反过来激活IRF3(interferon regulatory factor 3)和NF-κB(nuclear factor κ-light-chain-enhancer of activated B cells)等转录因子,促进编码I型干扰素和其他细胞因子和介导因子基因的转录来刺激更广泛的免疫反应。由恶性细胞和其他CDN产生的外源性2'3'-cGAMP,包括由细菌产生的那些和用于癌症免疫疗法的合成CDN,必须穿过细胞膜以激活靶细胞中的STING。这些带电的CDN如何通过脂质双层是未知的。

附:英文原文

Title:SLC19A1 transports immunoreactive cyclic dinucleotides

Author:Rutger D. Luteijn, Shivam A. Zaver, Benjamin G. Gowen, Stacia K. Wyman, Nick E. Garelis, Liberty Onia, Sarah M. McWhirter, George E. Katibah, Jacob E. Corn, Joshua J. Woodward, David H. Raulet 

Issue&Volume: 2019-09-11

Abstract:

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway3. The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP)4,5,6,7. This cyclic dinucleotide (CDN) activates STING8, which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2′3′-cGAMP produced by malignant cells9 and other CDNs, including those produced by bacteria10,11,12 and synthetic CDNs used in cancer immunotherapy13,14, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate–organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and—potentially—for some inflammatory diseases.

DOI: 10.1038/s41586-019-1553-0

Source: https://www.nature.com/articles/s41586-019-1553-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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