在Reactome数据库中，BioPAX途径由“ALPK1结合ADP-heptose”转化而来。 左到右 ALPK1结合ADP-heptose 在革兰氏阴性菌假结核耶尔森菌（Y.假）诱导的突变体21000转座子诱变研究表明，细菌转座子携带hldE突变已经受损的诱导核因子κB的活化能力（NF-κB）途径在人胚胎肾293T细胞系（HEK293T）（周P等。2018）。基因hldE为ADP -L-甘油基-β-d甘露 - 庚糖（ADP-庚糖），细菌代谢中间体在脂多糖（LPS）的生物合成，这是存在于所有的革兰氏阴性菌和革兰氏一些的生物合成必需阳性菌（唐W等一。2018）。此外，所需的ADP-庚糖相关的代谢物的生物合成相关基因的缺失，d甘油基-β-d甘露 - 庚糖-1,7-二磷酸（HBP），NF-κB的活化防止由假结核菌（周鹏等人。2018）。此外，合成的ADP-庚糖但不HBP，当加入到细胞外空间，诱导的NF-κB的活化和白细胞介素8（IL8或CXCL8）的分泌在HEK293T细胞（周P等。2018）。的荧光激活细胞分选（FACS）为主，全基因组CRISPR-Cas9屏幕上识别的α蛋白激酶1（ALPK1），肿瘤坏死因子（TNF-α）受体相关因子一个HEK293T NF-κB报道细胞系（TRAF）-interacting蛋白与所述叉头相关联的域（TIFA）和TRAF6作为NF-κB活化通过ADP-庚糖或假结核菌（周P等2018）诱导的介导物。ALPK1 - / - 或TIFA - / - HEK293T细胞显示废除NF-κB激活和细胞因子的表达。有缺陷的NF-κB活化中ADP-庚糖处理ALPK1 - / - 是由野生型ALPK1恢复HEK293T细胞而不是通过它的激酶失活突变体K1067M（周P等2018）。此外，ADP-庚糖刺激TIFA的共免疫沉淀与ALPK1（周P等。2018）。此外，ALPK1激酶需要在HEK293T细胞中的TIFA ADP-庚糖诱导的磷酸化活性，因此表明ALPK1作用TIFA的上游（周P等。2018）。 Similarly, ADP‐heptose sensing was ALPK1‐dependent during S. flexneri infection (Garcia-Weber D et al. 2018). These findings are supported by studies showing that cytosolic HBP, found in the bacteria Neisseria meningitidis, Shigella flexneri, Salmonella enterica serovar Typhimurium and Helicobacter pylori (H. pylori), induced activation of ALPK1-TIFA-dependent NF-κB signaling in host cells (Zimmermann S et al. 2017; Milivojevic M et al. 2017; Gaudet RG et al. 2017). In addition, HBP failed to directly activate ALPK1 (Garcia-Weber D et al. 2018; Zhou P et al. 2018); instead, HBP is converted by host-derived adenylyltransferases, such as nicotinamide nucleotide adenylyltransferases, to ADP-heptose 7-P, a substrate which activates ALPK1 and the downstream NF-κB response (Zhou P et al. 2018). ALPK1 contains a kinase domain (KD) and an α-helical domain linked by an unstructured region (Zhou P et al. 2018). Co-expression of the N-terminal domain (NTD) and KD of ALPK1 (ALPK1-NTD (1–473) and ALPK1-KD (959–1244), respectively) in HEK293T cells was sufficient to allow ADP-heptose or Y. pseudotuberculosis to induce activation of NF-κB and phosphorylation of TIFA (Zhou P et al. 2018). High-performance liquid chromatography (HPLC)- mass spectrometry (MS) fractionation of small-molecule extracts from His6–ALPK1-NTD purified from wild-type E. coli coupled with anti-pT9-TIFA immunoblotting and NF-κB luciferase reporter assays in HEK293T identified one active fraction that contained the presumed ADP-heptose ion. Direct binding of E. coli ΔhldE-derived apo-ALPK1-(NTD+KD) complex to ADP-heptose was detected by BioLayer Interferometry (BLI) assay in vitro (Zhou P et al. 2018). The structural studies revealed that a narrow pocket in ALPK1-NTD directly binds ADP-heptose (Zhou P et al. 2018). The ADP-heptose-binding residues are conserved in ALPK1 of other vertebrates. Introducing several mutations in respective residues at the NTD of ALPK1 impaired the ability of ALPK1 to activate NF-κB in response to ADP-heptose (Zhou P et al. 2018). The ADP-heptose binding to ALPK1 is thought to trigger conformational changes and stimulate the kinase domain of ALPK1 to phosphorylate and further activate TIFA, which eventually trigger activation of the downstream NF-κB pathway (Zhou P et al. 2018). Many Gram-negative bacteria induce host cytokine expression in a type III secretion system (T3SS)-dependent manner. T3SS of Y. pseudotuberculosis was required for ADP-heptose induced activation of NF-κB signaling, indicating that a bacterial injection system mediated ADP-heptose translocation to induce activation of ALPK1 upon Y. pseudotuberculosis infection (Zhou P et al. 2018). However, sensing of ADP-heptose by ALPK1 is not just limited to bacteria with T3SS. Burkholderia cenocepacia, enterotoxigenic E. coli, and diffuse-adhering E. coli, also stimulated NF-κB activation through the ALPK1-TIFA axis in an hldE-dependent manner in HEK293T cells (Zhou P et al. 2018). Further, TIFAsome formation and NF-kB activation could be triggered by H. pylori’s component secreted in a type IV secretion system (T4SS)-dependent fashion (Zimmermann S et al. 2017; Stein SC et al. 2017). Animal studies indicate that injection of ADP-heptose induced massive neutrophil recruitment with increased production of several NF-κB-dependent cytokines and chemokines in wild type (WT), but not in Alpk1-/- mice. On infection with B. cenocepacia, which triggers lung inflammation in WT, but not Alpk1-/- mice showed increased expression of NF-κB-dependent cytokines and chemokines in the lungs, which led to higher bacterial load in the lungs of Alpk-/-, but not WT, mice (Zhou P et al. 2018). Thus, in vitro and in vivo studies identified ADP-heptose as a bona fide bacterial immunomodulator which is sensed by cytosolic innate immune receptor ALPK1. 作者:Shamovsky, Veronica, 2019-05-17 评论:吉莱斯皮，马克E, 2019-06-03 邵锋，2019-07-08 编辑：Shamovsky，婆婆纳，2019年8月9日 ADP-heptose ADP-L-beta-D-heptose ADP-L-glycero-D-manno-heptose Reactome DB_ID：9645519 胞质 基因本体论 去:0005829 ADP-L甘油基d甘露 - 庚糖[飞燕：15915] ADP-L-glycero-D-manno-heptose ChEBI CHEBI: 15915 Reactome数据库ID Release 77 9645519 数据库标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9645519 Reactome R-ALL-9645519 6 Reactome稳定的标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9645519.6 Reactome //www.joaskin.com ALPK1 Alpha-protein激酶1 Reactome DB_ID：9645473 UniProt: Q96QP1 ALPK1 ALPK1 KIAA1527 腊克语 FUNCTION丝氨酸/苏氨酸 - 蛋白激酶，其检测细菌病原相关分子模式代谢物（的PAMP），并启动先天免疫应答，对病原体清除和适应性免疫的接合中的关键步骤（PUBMED：28877472，PUBMED：28222186，PUBMED：30111836）。特异性识别并结合ADP-d甘油基-β-d甘露 - 庚糖（ADP-庚糖），有效的存在于所有革兰氏阴性一个PAMP和一些革兰氏阳性菌（PUBMED：30111836）。ADP-庚糖结合刺激其激酶活性磷酸化并激活TIFA，引发促炎NF-κ-乙信令（PUBMED：30111836）。可在尿酸钠水合物（MSU）诱导的炎症通过介导的非常规肌球蛋白MYO9A的磷酸化参与（PUBMED：27169898）。也可通过介导的非常规肌球蛋白MYO1A的磷酸化发挥顶端蛋白转运中的作用（PUBMED：15883161）.ACTIVITY调控丝氨酸/苏氨酸蛋白激酶活性在ADP-d甘油-β-d甘露 - 庚糖（ADP-刺激庚）-binding.TISSUE特异性liver.SIMILARITY高表达属于蛋白超家族激酶。阿尔法型蛋白激酶家族。ALPK subfamily.CAUTION d甘油基-β-d甘露 - 庚糖-1,7-二磷酸（HBP）最初被认为构成了细菌病原相关分子模式代谢物（PAMP）触发ALPK1-TIFA先天immunune响应（PUBMED：28877472，考研：28222186）。然而，已经表明，ADP-d甘油基-β-d甘露 - 庚糖（ADP-庚糖）构成激活ALPK1的激酶活性的主要PAMP（PUBMED：30111836）。 智人 NCBI分类法 9606 UniProt Q96QP1 1 平等的 1244 平等的 Reactome数据库ID Release 77 9645473 数据库标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9645473 Reactome r - hsa - 9645473 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9645473.1 ALPK1: ADP庚糖 Reactome DB_ID: 9645521 1 1 Reactome数据库ID Release 77 9645521 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9645521 Reactome r - hsa - 9645521 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9645521.1 Reactome数据库ID Release 77 9645428 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9645428 Reactome r - hsa - 9645428 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9645428.1 29483275 PubMed. 2018年 d- sedoheptulose -7-磷酸是septacidin和潮霉素B的heptoses的常见前体 汤伟 郭,争艳彩 曹,Zhenju 王、最小值 李,鹏威 孟,湘西 赵,左学金 谢,Zhoujie Wang Wenzhao 周,艾华 卢,Chunbo 陈,兴企 Proc。国家的。学会科学。美国115:2818 - 2823 28877472 PubMed. 2017年 幽门螺杆菌IV型分泌系统触发ALPK1和tifa依赖性先天免疫反应 齐默尔曼，斯蒂芬妮 Pfannkuch, Lennart Al-Zeer,姆尼尔 Bartfeld,新浪 科赫曼努埃尔 刘，建平 Rechner,辛迪 瑟伦森，美克 Sokolova,奥尔加 Zamyatina,真主安拉 Kosma,保罗 毛雷尔，安德烈·P Glowinski, Frithjof Pleissner, Klaus-Peter 施密德，莫妮卡 Brinkmann, Volker 卡洛斯,亚历山大 迈克尔·瑙曼 洛特,马里昂 Machuy，尼古劳斯 迈耶托马斯˚F 细胞代表20:2384 - 2395 30111836 PubMed. 2018年 α -激酶1是细菌adp -七糖的胞浆内先天免疫受体 周,P 她,杨 董娜 李,彭 他，华彬 Borio,塞 吴Qingcui 陆,山 叮,) 曹,勇 徐悦 高,Wenqing 咚,Mengqiu 叮,京津城市 Wang Da-Cheng Zamyatina,真主安拉 邵，冯 自然561：122-126 28222186 PubMed. 2017年 ALPK1控制TIFA/ traf6依赖的天然免疫，对抗革兰氏阴性细菌七糖-1,7-二磷酸 Milivojevic, Milica 当热尔德，安妮 - 索菲 卡斯帕,Christoph亚历山大 Tschon, Therese Emmenlauer,马里奥 皮克,克劳丁 Schnupf，帕梅拉 Guignot,朱莉 Arrieumerlou,塞西尔 PLOS POAROG。13：e1006224 28715499 PubMed. 2017年 幽门螺杆菌由LPS内芯庚糖生物合成的中间代谢物的CagT4SS依赖性易位调制宿主细胞应答 斯坦因，萨斯基亚Ç 麦嘉华，尼娅 蝙蝠,西蒙H Murillo,塔蒂阿娜 Speidel,伊冯 库姆斯,尼娜 Josenhans,克里斯汀 公共科学图书馆Pathog。13:e1006514 30455202 PubMed. 2018年 ADP-heptose是新发现的福氏志贺氏菌的病原相关分子模式 Garcia-Weber,迭戈 当热尔德，安妮 - 索菲 Cornil，约翰 泰国,琳达 觉得,海洛薇兹 Zamyatina,真主安拉 Mulard,劳伦斯 Arrieumerlou,塞西尔 EMBO众议员19: 26068852 PubMed. 2015年 先天免疫。胞质检测细菌代谢物HBP可激活tifa依赖性先天免疫 Gaudet,瑞安G Sintsova，安娜 Buckwalter,卡洛琳米 梁,耐莉 科克伦艾伦。 李Jianjun 考克斯,安德鲁·D 莫法特,杰森 Gray-Owen,斯科特·D 科学348:1251-5