Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose
Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose
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α-激酶 1 是细菌 ADP-庚糖的胞质先天免疫受体
DOI：
10.1038/s41586-018-0433-3
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发表时间：
2018-09-06
期刊：
影响因子：
64.8
通讯作者：
Shao, Feng
中科院分区：
文献类型：
--
作者：
Zhou, Ping;She, Yang;Shao, Feng
模式识别受体对病原体相关分子模式 (PAMP) 的免疫识别通常会激活促炎性 NF-kappa B 信号传导 (1)。最近的研究表明，细菌代谢物 D-甘油-β-D-甘露庚糖 1,7-二磷酸 (HBP) 可以激活宿主细胞质中的 NF-kappa B 信号传导 (2-4)，但尚不清楚 HBP 是否是真正的 PAMP，并且尚未鉴定出同源模式识别受体。在这里，我们将假结核耶尔森氏菌转座子筛选与生化分析相结合，鉴定出 ADP-β-D-甘露庚糖 (ADP-Hep)，它介导 III 型分泌系统依赖性 NF-κ B 激活和细胞因子表达。 ADP-Hep（而非其他庚糖代谢物）可以进入宿主细胞质激活 NF-kappa B。CRISPR-Cas9 筛选显示，ADP-Hep 激活 NF-kappa B 涉及 ALPK1（α-激酶 1）-TIFA（具有叉头相关结构域的 TRAF 相互作用蛋白）轴。 ADP-Hep 直接结合 ALPK1 的 N 末端结构域，刺激其激酶结构域磷酸化并激活 TIFA。复合物中 ALPK1 和 ADP-Hep N 端结构域的晶体结构揭示了这种配体-受体识别过程的原子机制。 HBP 被宿主腺苷酸转移酶转化为 ADP-庚糖 7-P，其激活 ALPK1 的程度低于 ADP-Hep。 ADP-Hep（但不是 HBP）单独或在细菌感染期间诱导小鼠 Alpk1 依赖性炎症。我们的研究结果将 ALPK1 和 ADP-Hep 分别确定为模式识别受体和有效的免疫调节剂。
Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-kappa B signalling(1). Recent studies indicate that the bacterial metabolite D-glycero-beta-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-kappa B signalling in host cytosol(2-4), but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-beta-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-kappa B activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-kappa B. A CRISPR-Cas9 screen showed that activation of NF-kappa B by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.