Alpha-蛋白激酶 1 信号通路
中文名称
通路描述
病原体相关分子模式（PAMPs）通过模式识别受体（PRR）的免疫识别常激活促炎核因子 kappa B（NF-κB）信号。脂多糖（LPS）是革兰氏阴性细菌产生的众所周知的 PAMP。LPS 被 toll like receptor 4（TLR4）识别，并强烈激活 NF-κB 炎症反应（Akashi S et al. 2003）。LPS 也在细胞质中被小鼠 caspase-11 和人类 caspase-4、caspase-5 识别，这些酶刺激细胞死亡的一种促炎形式，即焦亡（Kayagaki N et al. 2011; Shi J et al. 2015）。LPS 生物合成中的关键代谢中间体，d-glycero-β-d-manno-heptose 1,7-bisphosphate（HBP）和 ADP L-glycero-β-d-manno-heptose（ADP-heptose），据报道可激活 NF-κB 通路并触发先天免疫反应（Milivojevic M et al. 2017; Zimmermann S et al. 2017; Zhou P et al. 2018; García-Weber D; 2018）。ADP-heptose 但不能 HBP 自主进入宿主细胞（Zhou P et al. 2018）。在感染期间，ADP-heptose 或 HBP 转运到宿主细胞质，其存在被 alpha-蛋白激酶 1（ALPK1）感知（Zimmermann S et al. 2017; Zhou P et al. 2018）。ADP-heptose 直接与 ALPK1 结合并激活 ALPK1（Garcia-Weber D et al. 2018; Zhou P et al. 2018）；相反，HBP 由宿主来源的腺苷酰转移酶，如烟酰胺核苷腺苷酰转移酶，转化为 ADP-heptose 7-P，该底物可随后激活 ALPK1（Zhou P et al. 2018）。ADP-heptose 与 ALPK1 的结合被认为触发构象变化并刺激 ALPK1 的激酶域（Zhou P et al. 2018）。ALPK1 激酶活性进而导致肿瘤坏死因子（TNF-α）受体相关因子（TRAF）-相互作用蛋白（TIFA）的磷酸化依赖寡聚化，TIFA 包含 forkhead-associated 域（Gaudet RG et al. 2017; Stein SC et al. 2017; Gall A et al. 2017; Zimmermann S et al. 2017; Milivojevic M et al. 2017; Zhou P et al. 2018）。该 TIFA 寡聚化信号平台被称为 TIFAsome。TIFAsome 激活的 TAK1 诱导 NF-κB 核转位和促炎基因表达。ALPK1-TIFA 信号通路已在人胚胎肾细胞、肠上皮细胞、胃细胞和宫颈癌细胞中鉴定（Gaudet RG et al. 2015, 2017; Stein SC et al. 2017; Gall A et al. 2017; Zimmermann S et al. 2017; Milivojevic M et al. 2017; Zhou P et al. 2018）。体内研究表明，ADP-heptose 和 Burkholderia cenocepacia 在野生型（WT）小鼠中引发大规模炎症反应，产生多种 NF-κB 依赖性细胞因子和趋化因子，而在 Alpk1-/-小鼠中未观察到（Zhou P et al. 2018）。
英文描述
Alpha-protein kinase 1 signaling pathway Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRR) often activates proinflammatory nuclear factor kappa B (NF-κB) signalling. Lipopolysaccharide (LPS) is a well-known PAMP produced by gram-negative bacteria. LPS is recognized by toll like receptor 4 (TLR4) and is a strong activator of NF-κB inflammatory responses (Akashi S et al. 2003). LPS is also recognized in the cytosol by mouse caspase-11 and related human caspase-4 and caspase-5, which stimulate pyroptosis, a proinflammatory form of cell death (Kayagaki N et al. 2011; Shi J et al. 2015). Key metabolic intermediates in LPS biosynthesis, d-glycero-β-d-manno-heptose 1,7-bisphosphate (HBP) and ADP L-glycero-β-d-manno-heptose (ADP-heptose) were reported to activate the NF-κB pathway and trigger the innate immune responses (Milivojevic M et al. 2017; Zimmermann S et al. 2017; Zhou P et al. 2018; GarcÃa-Weber D; 2018). ADP-heptose but not HBP can enter host cells autonomously (Zhou P et al. 2018). During infection, ADP-heptose or HBP translocate into the host cytosol where their presence is sensed by alpha-protein kinase 1 (ALPK1) (Zimmermann S et al. 2017; Zhou P et al. 2018). ADP-heptose directly binds and activates 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 can then activate ALPK1 (Zhou P et al. 2018). The ADP-heptose binding to ALPK1 is thought to trigger conformational changes and stimulate the kinase domain of ALPK1 (Zhou P et al. 2018). ALPK1 kinase activity in turn leads to the phosphorylation-dependent oligomerization of the tumor necrosis factor (TNF-α) receptorâassociated factor (TRAF)âinteracting protein with the forkhead-associated domain (TIFA) (Zimmermann S et al. 2017; Zhou P et al. 2018). This process activates TRAF6 oligomerization and ubiquitination, and the recruitment of transforming growth factor β-activated kinase 1 (TAK1)-binding protein 2 (TAB2), a component of the TAK1 (MAP3K7) complex (Ea CK et al. 2004; Gaudet RG et al. 2017). This TIFA oligomer signaling platform was given the term: TIFAsome. TIFAsome-activated TAK1 induces NF-κB nuclear translocation and proinflammatory gene expression. The ALPK1-TIFA signaling pathway has been identified in human embryonic kidney cells, intestinal epithelial cells, gastric cells and cervical cancer cells (Gaudet RG et al. 2015, 2017; Stein SC et al. 2017; Gall A et al. 2017; Zimmermann S et al. 2017; Milivojevic M et al. 2017; Zhou P et al. 2018). In vivo studies demonstrate that ADP-heptose and Burkholderia cenocepacia trigger massive inflammatory responses with increased production of several NF-κB-dependent cytokines and chemokines in wild type (WT), but not in Alpk1-/- mice (Zhou P et al. 2018).This Reactome module describes ALPK1 as a cytosolic innate immune receptor for bacterial ADP-heptose.
所含基因
11 个基因